Compstatin analogs and their medical uses

Abstract

We describe compstatin analogs that have improved binding and complement inhibitory activity compared to the 13-amino acid compstatin peptide (ICVQDWGHHRCT(cyclic C2-C12)), and that further possess useful physicochemical properties, particularly increased solubility. These analogs include variants with an isoleucine residue at position 3 instead of the wild-type valine residue, which provides compstatin peptides with improved binding and complement inhibitory activity and also allows for the introduction of other modifications that can enhance solubility, such as introducing a charged or polar amino acid at position 9 and / or introducing N- and / or C-terminal sequences.

Description

Technical Field

[0001] The present invention relates to inhibiting the activation of the complement cascade in the body, and more particularly to compstatin analogs that can bind to C3 protein and inhibit complement activation. The present invention also relates to the medical use of compstatin analogs, in particular for the treatment of conditions characterized by unwanted activation of the complement cascade, such as autoimmune and inflammatory diseases.

Background Art

[0002] The human complement system plays a powerful role in defense against pathogenic organisms and in mediating immune responses. Complement is activated via three distinct pathways, namely the classical pathway, the lectin pathway, and the alternative pathway. The major activation event common to all three pathways is the proteolytic cleavage of the central protein of the complement system, C3, into the activation products C3a and C3b by C3 convertase. The generation of these fragments leads to the opsonization of pathogenic cells by C3b and iC3b, a process that renders them susceptible to phagocytosis or clearance and results in the activation of immune cells via interaction with complement receptors (Markiewski & Lambris, 2007, Am. J. Pathol., 171: 715-727). The deposition of C3b on target cells also induces the formation of new convertase complexes, thereby initiating an autoamplification loop. Aggregates of proteins bound to plasma and cell surfaces carefully regulate complement activation to prevent self-attack of host cells by the complement cascade. However, excessive activation or inappropriate regulation of complement can cause a number of pathologies, ranging from autoimmune diseases to inflammatory diseases (Holers, 2003, Clin. Immunol., 107: 140-51; Markiewski & Lambris, 2007, supra; Ricklin & Lambris, 2007, Nat. Biotechnol., 25: 1265-75; Sahu et al., 2000, J. Immunol., 165: 2491-9). Therefore, the development of therapeutic complement inhibitors is highly desirable. In this context, C3 and C3b have emerged as promising targets because of their central role in the cascade, which allows for the simultaneous inhibition of complement initiation, amplification, and downstream activation (Ricklin & Lambris, 2007, supra).

[0003] Compstatin was first identified as a 27 - amino - acid peptide and was the first non - host - derived complement inhibitor shown to be able to block all three activation pathways (Sahu et al., 1996, J. Immunol., 157: 884 - 91; U.S. Patent No. 6,319,897). Compstatin has been shown to be cleavable to a 13 - amino - acid peptide without loss of activity. However, further attempts to cleave this peptide resulted in loss of activity. The sequence of the 13 - amino - acid cleaved (or “core”) compstatin peptide is Ile1 - Cys2 - Val3 - Val4 - Gln5 - Asp6 - Trp7 - Gly8 - His9 - His10 - Arg11 - Cys12 - Thr13 - NH 2 where Cys2 and Cys12 are disulfide - bonded. This cyclic tridecapeptide binds to C3 (and fragments of C3), thereby inhibiting the activation of the downstream complement cascade and preventing the cleavage of native C3 by C3 convertase. Its inhibitory effect has been confirmed by studies using a series of experimental models that point to its potential as a therapeutic agent (Fiane et al., 1999a, Xenotransplantation, 6: 52 - 65; Fiane et al., 1999b, Transplant Proc., 31:934 - 935; Nilsson et al., 1998, Blood, 92: 1661 - 1667; Ricklin & Lambris, 2008, Adv.Exp.Med..Biol., 632: 273 - 292; Schmidt et al., 2003, J. Biomed. Mater. Res., A66: 491 - 499; Soulika et al., 2000, Clin.Immunol., 96: 212 - 221).

[0004] Progressive optimization of the 13 - amino - acid compstatin peptide has led to analogs with improved biological activity (Ricklin & Lambris, 2008, supra; WO2004 / 026328; WO2007 / 062249, WO2013 / 036778, WO2014 / 100407).

[0005] In previous structure-activity studies, the important features of this molecule have been identified as the cyclicity of the compstatin peptide and the presence of β-turns and hydrophobic clusters (Morikis et al., 1998, Protein Sci., 7: 619-627; WO99 / 13899; Morikis et al., 2002, J. Biol. Chem., 277:14942-14953; Ricklin & Lambris, 2008, supra). Hydrophobic residues at positions 4 and 7 have been found to be particularly important, and modification with their unnatural amino acids generated analogs with an activity 264-fold improved over the original compstatin peptide (Katragadda et al., 2006, J. Med. Chem., 49: 4616-4622; WO2007 / 062249d). Further attempts to optimize compstatin for use in the treatment of eye disorders are described in WO2007 / 044668.

[0006] Previous optimization steps, including combinatorial screening studies, solution structures, and computational models (Chiu et al., 2008, Chem. Biol. Drug Des., 72: 249-256; Mulakala et al., 2007, Bioorg. Med. Chem., 15: 1638-1644; Ricklin & Lambris, 2008, supra), and the publication of the co-crystal structure of compstatin complexed with complement fragment C3c (Janssen et al., 2007, J. Biol. Chem., 282: 29241-29247; WO2008 / 1539) provided a basis for initiating rational optimization. The crystal structure revealed a shallow binding site at the interface of macroglobulin (MG) domains 4 and 5 of C3c, and showed that 9 out of 13 amino acids are directly involved in binding via either hydrogen bonds or hydrophobic interactions. Compared to the structure of the compstatin peptide in solution (Morikis et al., 1998, supra), the bound form of compstatin underwent a conformational change involving a shift in the position of the β-turn from residues 5-8-11 to 8-11 (Janssen et al., 2007, supra; WO2008 / 153963).

[0007] In view of AMD, C3G, PNH and its therapeutic potential in other diseases, for example, to achieve higher activity and / or to modulate pharmacokinetic properties such as increased half-life and / or physicochemical properties such as increased solubility, further optimization of compstatin analogs remains a problem in the art. SUMMARY OF THE INVENTION

[0008] Generally, the present invention is based on research to develop a new family of compstatin analogs having improved binding and complement inhibitory activity compared to the 13 - amino acid compstatin peptide (ICVVQDWGHHRCT (cyclic C2 - C12)). In some cases, these compstatin analogs further have useful physicochemical properties such as increased solubility. In particular, the inventors have found that introducing an isoleucine residue at the 3 - position instead of the wild - type valine residue results in a compstatin peptide with improved binding and complement inhibitory activity. The inventors have further found that introducing isoleucine at the 3 - position allows for the introduction of other modifications, such as introducing glutamic acid at the 6 - position, introducing a specific charged or polar amino acid at the 9 - position, and / or introducing an N - terminal sequence and / or a C - terminal sequence, which can increase solubility. Examples of such additional modifications include substituting Ile at the 1 - position with Tyr, Phe or Sar, substituting Val at the 4 - position with a Trp analog (as described herein), substituting Asp at the 6 - position with Glu, substituting His at the 9 - position with Ala, Glu, Asp, Lys, Ser or Arg, substituting Arg at the 11 - position with Ser, and substituting Thr at the 13 - position with Ser, Glu, Sar or Ile. Preferred compstatin peptides containing one or more of these modifications have improved solubility, for example, compared to the 13 - amino acid compstatin peptide (ICVVQDWGHHRCT (cyclic C2 - C12)). Further examples of these compstatin peptides combine the modification at the 9 - position with an extension to the N - terminal and / or C - terminal of the peptide.

[0009] Accordingly, the present invention provides a compound of the formula: Y1 - R1 - X1 - C - I - X4 - Q - X6 - W - X8 - X9 - H - X11 - C - X13 - R2 - Y2 (Formula I) [wherein, Y1 is hydrogen, acetyl or a lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, F, V, Y, 1-Me-Trp, D-Trp, N-Me-Trp, 1-For-Trp, 1-Nal, 2-Nal, 5-Me-Trp, Bpa or 2-Igl; X6 is E, K or D; X8 is G or Sar; X9 is H, A, E, D, K, R or S; X11 is R, S or K; X13 is T, S, E, F, H, K, Sar, G, I, D, N-Me-Ile or N-Me-Thr; Y2 is NH 2 , OH or the lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3, Peg4, or 8-aminooctanoyl; or derivatives thereof; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof] a compstatin analog represented by the compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, the compstatin analog optionally has a lipophilic group Φ covalently attached to the side chain of one or more amino acid residues, or a pharmaceutically acceptable salt and / or solvate thereof is provided.

[0010] In some embodiments, X11 is R or S.

[0011] In certain embodiments, when the lipophilic group Φ is linked to the side chain of an amino acid residue, the residue is a residue at the X1, X11 or X13 position, or a residue of R1 or R2. It may be a lysine residue. For example, it may be a lysine residue at the X11 or X13 position, or a lysine residue of R1 or R2.

[0012] In certain embodiments, Y1 is hydrogen or acetyl.

[0013] In certain embodiments, Y2 is NH 2 or OH.

[0014] In some embodiments, the compstatin analog contains at least one lipophilic group Φ, for example exactly one lipophilic group Φ.

[0015] In some embodiments, the compstatin analog does not contain a lipophilic group Φ.

[0016] The present invention further provides a formula: Y1-R1-X1-C-I-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula II) [wherein, Y1 is hydrogen, acetyl, or a lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, Y, 2-Nal, 1-Nal or 1-Me-Trp; X6 is E or D; X8 is G or Sar; X9 is A, E, D, K or S; X11 is R, S or K; X13 is T, S, E, I, Sar, K, G or N-Me-Ile; Y2 is NH 2 , OH or a lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof] A compstatin analog represented by The compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, The compstatin analog optionally provides the above analog having a lipophilic group Φ covalently attached to the side chain of one or more amino acids, or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] In some embodiments, X11 is R or S.

[0018] In one embodiment, when the lipophilic group Φ is linked to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue of R1 or R2. It may be a lysine residue. For example, it may be a lysine residue at position X13, or a lysine residue of R1 or R2.

[0019] In one embodiment, Y1 is hydrogen or acetyl.

[0020] In one embodiment, Y2 is NH 2 or OH.

[0021] In some embodiments, the compstatin analog comprises at least one lipophilic group Φ, for example exactly one lipophilic group Φ.

[0022] In some embodiments of this formula, the compstatin analog does not contain the lipophilic group Φ.

[0023] The present invention further provides a compound of the formula: Y1-R1-X1-C-I-X4-Q-X6-W-G-X9-H-X11-C-X13-R2-Y2 (Formula III) [wherein, Y1 is hydrogen, acetyl or the lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, Y, 1-Nal, 2-Nal or 1-Me-Trp; X6 is E or D; X9 is A, E, D, K or S; X11 is R, S or K; X13 is T, I, S, E, K or Sar; Y2 is NH 2 , OH or the lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms, or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof] and is an analog represented by the compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, the compstatin analog optionally provides the above analog having a lipophilic group Φ covalently attached to the side chain of one or more amino acids, or a pharmaceutically acceptable salt and / or solvate thereof.

[0024] In some embodiments, X11 is R or S.

[0025] In certain embodiments, when the lipophilic group Φ is linked to the side chain of an amino acid residue, the residue is a residue at the X1, X11 or X13 position, or a residue of R1 or R2. It may be a lysine residue. For example, it may be a lysine residue at the X11 or X13 position, or a lysine residue of R1 or R2.

[0026] In certain embodiments, Y1 is hydrogen or acetyl.

[0027] In certain embodiments, Y2 is NH 2 or OH.

[0028] In some embodiments, the compstatin analog contains at least one lipophilic group Φ, for example, exactly one lipophilic group Φ.

[0029] In some embodiments of this formula, the compstatin analog does not contain a lipophilic group Φ.

[0030] The compstatin analog has the formula: Y1-R1-X1-C-I-X4-Q-X6-W-G-X9-H-R-C-X13-R2-Y2 (Formula IV) [wherein, Y1 is hydrogen, acetyl or a lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, Y, 1-Nal, 2-Nal or 1-Me-Trp; X6 is E or D; X9 is A, E, D, K or S; X13 is T, S, E or Sar; Y2 is NH 2 , OH or a lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms, or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof; The compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, The compstatin analog may optionally be represented by the above analog having a lipophilic group Φ covalently attached to the side chain of one or more amino acids, or a pharmaceutically acceptable salt and / or solvate thereof.

[0031] In certain embodiments, when the lipophilic group Φ is linked to the side chain of an amino acid residue, the residue is a residue at position X1, X11 or X13, or a residue of R1 or R2. It may be a lysine residue. For example, it may be a lysine residue at position X13, or a lysine residue of R1 or R2.

[0032] In certain embodiments, Y1 is hydrogen or acetyl.

[0033] In certain embodiments, Y2 is NH 2 or OH.

[0034] In some embodiments, the compstatin analog comprises at least one lipophilic group Φ, for example exactly one lipophilic group Φ.

[0035] In some embodiments of this formula, the compstatin analog does not contain a lipophilic group Φ.

[0036] In some embodiments of the above formula, X6 is D.

[0037] In one aspect, a compstatin analog having no lipophilic group Φ has the following formula: Y1-R1-X1-C-I-X4-Q-X6-W-G-X9-H-R-C-X13-R2-Y2 (Formula V) [wherein, Y1 is hydrogen or acetyl; X1 is Y or F; X4 is W, Y, 1-Me-Trp; X6 is E or D; X9 is A, E or K; X13 is T, E or Sar; Y2 is NH 2 or OH; R1 is absent or a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms, or Peg3, Peg4, or 8-aminooctanoyl, or their derivatives; R2 is absent or a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or their derivatives] The compstatin analog according to claim 1, represented by The compstatin analog may be the above analog having a disulfide bond between the cysteine residues at positions 2 and 12, or a pharmaceutically acceptable salt and / or solvate thereof.

[0038] The compstatin analog has the formula: Y1-R1-X1-C-I-[1-Me-Trp]-Q-X6-W-G-E-H-R-C-X13-R2-Y2 (Formula VI) [wherein, Y1 is hydrogen or acetyl; X1 is Y or F; X6 is E or D; X13 is T, E or Sar; Y2 is NH 2 or OH; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms, or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof; R2 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof and can be represented by The Compstatin analog is the above analog having a disulfide bond between the cysteine residues at positions 2 and 12, or a pharmaceutically acceptable salt and / or solvate thereof.

[0039] In the above formula, X6 may be D or E.

[0040] In some embodiments, the Compstatin analog has the formula: Y1-R1-X1-C-I-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula VII) [wherein, Y1 is hydrogen, acetyl or the lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, 1-Me-Trp, 1-Nal or 2-Nal; X6 is E, K or D; X8 is G or Sar; X9 is H, A, E, D, K, R or S; X11 is R, S, K or K * ; X13 is T, S, E, Sar or N-Me-Ile; Y2 is NH 2 or OH; R1 and R2 may be any of the above formulas or as defined elsewhere in this specification and have.

[0041] In some embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, K, K * , S, Y, or their corresponding D-forms; and / or R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, K, K * , P, S, Peg3, γGlu, 8-aminooctanoyl, or their corresponding D-forms; * indicates that the amino acid residue has a lipophilic group Φ covalently bonded to its side chain.

[0042] Compstatin analogs may desirably contain at least one lipophilic group Φ, for example exactly one lipophilic group Φ. Alternatively, they may not contain a lipophilic group Φ.

[0043] In an alternative embodiment, a compstatin analog containing a lipophilic group Φ is Y1-R1-X1-C-I-X4-Q-X6-W-X8-X9-H-X11-C-X13-R2-Y2 (Formula VIII) [wherein, Y1 is hydrogen, acetyl or a lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, Y, 2-Nal, 1-Nal or 1-Me-Trp; X6 is E or D; X8 is G or Sar; X9 is A, E, D, K or S; X11 is R, S or K * ; X13 is T, S, E, I, Sar, K, G or N-Me-Ile; Y2 is NH 2, OH, or a lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V, or Sar, or their corresponding D-forms; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg 3, Peg4, or 8-aminooctanoyl, or derivatives thereof and can be represented by * indicates that the amino acid residue has a lipophilic group Φ covalently bonded to its side chain, the compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, the compstatin analog is the above analog containing at least one lipophilic group Φ, for example exactly one lipophilic group Φ, or a pharmaceutically acceptable salt and / or solvate thereof.

[0044] In some embodiments, Y2 is NH 2 or OH.

[0045] The compstatin analog has the formula: Y1-R1-X1-C-I-X4-Q-X6-W-G-X9-H-X11-C-X13-R2-Y2 (Formula IX) [wherein, Y1 is hydrogen, acetyl, or a lipophilic group Φ; X1 is I, Y, F, or Sar; X4 is W, V, Y, 1-Nal, 2-Nal, or 1-Me-Trp; X6 is E or D; X9 is A, E, D, K, or S; X11 is R, S, or K * ; X13 is T, I, S, E, K, or Sar; Y2 is NH 2, OH or a lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V or Sar, or their corresponding D-forms; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof; and can be represented by analogs, * which indicates that the amino acid residue has a lipophilic group Φ covalently bonded to its side chain, the Compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, the Compstatin analog is the above analog containing at least one lipophilic group Φ, for example exactly one lipophilic group Φ, or a pharmaceutically acceptable salt and / or solvate thereof.

[0046] In certain embodiments, Y2 is NH 2 or OH.

[0047] The Compstatin analog has the formula: Y1-R1-X1-C-I-X4-Q-X6-W-G-X9-H-R-C-X13-R2-Y2 (Formula X) [wherein, Y1 is hydrogen, acetyl or a lipophilic group Φ; X1 is I, Y, F or Sar; X4 is W, V, 1-Nal, 2-Nal or 1-Me-Trp; X6 is E or D; X9 is A, E, D, K or S; X13 is T, S, E or Sar;. Y2 is NH 2 , OH or a lipophilic group Φ; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V or Sar, or their corresponding D-forms; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof] A mimetic represented by * wherein the amino acid residue has a lipophilic group Φ covalently attached to its amino acid side chain, the compstatin mimetic has a disulfide bond between the cysteine residues at positions 2 and 12, the compstatin mimetic contains at least one lipophilic group Φ, such as exactly one lipophilic group Φ, or a pharmaceutically acceptable salt and / or solvate thereof.

[0048] In certain embodiments, Y2 is NH 2 or OH.

[0049] In any of the above formulas, X6 may be D. Alternatively, X6 may be E.

[0050] In any of the above formulas, X1 may be Y. Alternatively, X1 may be F.

[0051] In any of the above formulas, X13 may be Sar. Alternatively, X13 may be T.

[0052] Additionally or alternatively, any of the above formulas may include one of the following combinations of residues: X4 is 1-Me-Trp and X9 is E. X1 is F, X4 is 1-Me-Trp and X9 is E. X4 is 1-Me-Trp, X9 is E, and X13 is Sar. X4 is 1-Me-Trp, X9 is E, and X13 is T. X4 is 1-Me-Trp, X6 is D, X9 is E, and X13 is Sar. X4 is 1-Me-Trp, X6 is E, X9 is E, and X13 is Sar. X4 is 1-Me-Trp, X6 is D, X9 is E, and X13 is T. X4 is 1-Me-Trp, X6 is E, X9 is E, and X13 is T.

[0053] The Compstatin analog is of the formula: Y1-R1-X1-C-I-[1-Me-Trp]-Q-X6-W-G-E-H-R-C-X13-R2-Y2 (Formula XI) [wherein, Y1 is hydrogen or acetyl; X1 is Y or F; X6 is E or D; X13 is T, E or Sar; Y2 is NH 2 or OH; R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V or Sar, or their corresponding D-forms; R2 is absent or is a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, K * , F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3 or Peg4; or 8-aminooctanoyl, or derivatives thereof] and is an analog represented by * indicating that the amino acid residue has a lipophilic group Φ covalently bonded to its side chain, the Compstatin analog has a disulfide bond between the cysteine residues at positions 2 and 12, The Compstatin analog is the above-mentioned analog containing at least one lipophilic group Φ, for example, exactly one lipophilic group Φ, or a pharmaceutically acceptable salt and / or solvate thereof.

[0054] In some embodiments, the 13-mer peptide portion (X1-X13) of the Compstatin analog is as follows: [Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]; [Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)T; [Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)T; [Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]; [Sar]C(1)IWQDWGEHRC(1)T; FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]; FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)T; FC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]; FC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]; FC(1)I[1-Me-Trp]QDWGEHRC(1)E; FC(1)I[1-Me-Trp]QDWGEHRC(1)S; FC(1)I[1-Me-Trp]QDWGEHRC(1)T; FC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]; FC(1)I[1-Nal]QDWGEHRC(1)T; FC(1)I[2-Nal]QDWGEHRC(1)T; FC(1)IWQDWGEHRC(1)[Sar]; FC(1)IWQDWGEHRC(1)T; IC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)[N-Me-Ile]; IC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]; IC(1)I[1-Me-Trp]QDWGEHRC(1)T; IC(1)I[2-Nal]QDWGEHRC(1)[Sar]; IC(1)IWQDWGAHRC(1)E; IC(1)IWQDWGAHRC(1)T; IC(1)IWQDWGAHSC(1)T; IC(1)IWQDWGDHRC(1)T; IC(1)IWQDWGEHRC(1)[Sar]; IC(1)IWQDWGEHRC(1)E; IC(1)IWQDWGEHRC(1)S; IC(1)IWQDWGEHRC(1)T; IC(1)IWQDWGEHSC(1)T; IC(1)IWQDWGKHRC(1)T; IC(1)IWQDWGRHRC(1)T; IC(1)IWQDWGSHRC(1)T; IC(1)IWQEWGEHRC(1)T; IC(1)IWQKWGAHRC(1)T; IC(1)IWQKWGEHRC(1)T; YC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]; YC(1)I[1-Me-Trp]QDWGEHRC(1)T; YC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]; YC(1)I[2-Nal]QDWGEHRC(1)T; YC(1)IWQDWGEHRC(1)T; YC(1)I[1-Me-Trp]QDWGEH[K * C(1)[Sar]; and YC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar] having a sequence selected from *indicates that the amino acid residue has a lipophilic group Φ covalently bonded to its side chain.

[0055] In certain embodiments, R1 is absent or is 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, R, V or Sar, or their corresponding D-type sequences, and / or R2 can be 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, R, V or Sar, or their corresponding D-types.

[0056] For example, R1 is selected from ESSA, AKGE, ASSE, ASES, GSAE, ESSE, ESGA, SEG, GES, ESS, EGSA, ESE, EGE, ESA, SAE, SGA, YLEA, GSA, KEK, EKG, ES, AS, SE, SA or E, and / or R2 is selected from GAES, EYGS, EGYA, EAGS, EAKS, EKSA, EGGS, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, ESG, EAG, GAE, EGEA, EGE, EA, E, GE, EG, EKE or EKP.

[0057] In alternative embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-types, or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof.

[0058] In certain embodiments, R1 is absent or is a sequence of 1 to 6 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V or Sar, or their corresponding D-types.

[0059] For example, R1 can be absent or be a sequence of 1 to 6 amino acid residues selected from A, E, G, K, S and Y, or their corresponding D-types.

[0060] The lipophilic group Φ can be covalently linked to the side chain of one or more residues in Y1, particularly the side chain of a lysine residue (K * which may be referred to as). It may be desirable for the residue having Φ to be at the N-terminus of Y1.

[0061] Examples of the sequence of the R1 group include {d}Y, EGSE, AGSE, SASE, EYSE, GSE, ASE, ESSA, KGSA, AKGE, ASGE, ASSE, ASES, GSAE, ESSE, ESGA, SEG, GES, ESS, EGSA, ESE, EGE, ESA, SAE, SGA, YLEA, GSA, KEK, EKG, ES, RS, SR, AE, TE, KE, GE, FE, YE, AS, SE, RS, SR, SA, GE, S, Y and E.

[0062] In certain embodiments, R1 is 2 amino acid residues in length, for example, AE, TE, KE, GE, FE, YE, AS, SE, SA, or GE; preferably, AE, TE, KE, GE, FE, YE, SE, or GE.

[0063] In certain embodiments, R1 is 1 amino acid in length, for example, E.

[0064] As described above, the lipophilic group Φ covalently binds to the side chain of one or more residues in Y1, particularly the side chain of a lysine residue (K * which may be referred to as) to obtain, for example, the sequence K * GSA.

[0065] R2 may be absent or a sequence of 1 to 8 amino acid residues selected from A, E, G, L, K, F, P, S, T, W, Y, R, V, Sar, εLys, γGlu, βAsp, or βAla, or their corresponding D-forms; or Peg3, Peg4, or 8-aminooctanoyl, or derivatives thereof.

[0066] For example, R2 may be absent, or may be selected from A, E, G, K, S, γGlu, Peg3, or 8-aminooctanoyl, or may be a sequence of 1 to 8 amino acid residues selected from A, E, G, K, and S.

[0067] When K is present in R2, it may be desirable for K to be present at the C-terminus of R2.

[0068] The lipophilic group Φ may be covalently bonded to the side chain of one or more residues in Y2, particularly the side chain of a lysine residue. In some cases, it may be desirable for the residue having Φ to be at the C-terminus of Y2.

[0069] Examples of the sequence of the R2 group include EGASGSG, EGAGSG, EGASAG, EGAGAG, EGESGSG, EGEGSG, EGESAG, EGEGAG, EK[γGlu]AK, EGEGG, EGAGG, EGESS, GAESK, EGAK, EGEK, EGG, EGK, EGKK, EGS, EK, EGA, EGAK, EK[γGlu], EK[γGlu]-K, EGE-[Peg3, EGE[Peg3]-K, EGE[Peg3][Peg3], EGE[Peg3][Peg3]-K, EGE[Peg3][Peg3][Peg3], GESESE, GAESES, EGESES, EGESESK, EGE[Peg3]-ES, EGE[Peg3]-ESK, GESESE, EGE-[8-aminooctanoyl], EGE-[8-aminooctanoyl]-K, EGE-[8-aminooctanoyl]-EK, EGEGGG, EGEGGGK, EK[γGlu]GGG, EK[γGlu]GGGK, EGE-[8-aminooctanoyl]-E, GAES, EYGS, EGYA, EAGS, EAKS, EKSA, ESGA, EGG, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, EGK,, ESG, EAG, GAE, EGEA, EGE, EA, E, S, GE, GEK, EG, EA, EKE, and EKP.

[0070] Examples of the sequence of the R2 group include EGASGSG, EGAGSG, EGASAG, EGAGAG, EGESGSG, EGEGSG, EGESAG, EGEGAG, EK[γGlu]AK, EK[γGlu]A, EGEGG, EGAGG, EGESS, GAESK, EGAK, EGEK, EGG, EGK, EGKK, EGS, EK, EGA, EGAK, EK[γGlu], EK[γGlu]-K, EGE[Peg3], EGE[Peg3]-K, EGE[Peg3][Peg3], EGE[Peg3][Peg3]-K, EGE[Peg3][Peg3][Peg3], EGE[Peg3][Peg3][Peg3]-K GESESE, GAESES, EGESES, EGESESK, EGE[Peg3]-ES, EGE[Peg3]-ESK, GESESE, EGE-[8-aminooctanoyl], EGE-[8-aminooctanoyl]-K, EGE-[8-aminooctanoyl]-EK, EGEGGG, EGEGGGK, EK[γGlu]GGG, EK[γGlu]GGGK, EGE-[8-aminooctanoyl]-E, E[Peg3][Peg3], E[Peg3][Peg3]-K, EA[Peg3][Peg3], EA[Peg3][Peg3]-K, GAES, EYGS, EGYA, EAGS, EAKS, EKSA, ESGA, EGGS, EGGA, ESSG, ESAG, GEES, AEES, ESEG, AEGS, ESGS, SEGA, SEG, EGK, ESG, EAG, GAE, EGEA, EGE, EA, E, S, GE, GEK, EG, EA, EKE and EKP are included.

[0071] As described above, the lipophilic group Φ is one or more side chains of the residues in Y2, particularly, covalently bonded to the side chain, for example, the sequence EK[γGlu]AK * , EGKK * , EK[γGlu]K * , EGE[Peg3]-K * ,, EGESESK * , EGE[Peg3]-ESK * , EGE-[8-aminooctanoyl]-K * , EGE-[8-aminooctanoyl]-EK * , EGEGGGK * , EK[γGlu]GGGK* 、EGE[Peg3][Peg3]-K * 、GAESK * 、EGAK * 、EGEK * 、EGK * EGE[Peg3]-ESK * 、GESESEK * 、GEK * or EK * can be obtained.

[0072] As described above, the lipophilic group Φ covalently binds to one or more residues in Y2, particularly the side chain of the lysine residue side chain, for example, EK[γGlu]AK * 、EGKK * 、EK[γGlu]K * 、EGE[Peg3]-K * 、EGESESK * 、EGE[Peg3]-ESK * 、EGE-[8-aminooctanoyl]-K * 、EGE-[8-aminooctanoyl]-EK * 、EGEGGGK * 、EK[γGlu]GGGK * 、EGE[Peg3][Peg3]-K * 、EGE[Peg3][Peg3][Peg3]-K * 、E[Peg3][Peg3]-K * 、EA[Peg3][Peg3]-K * 、GAESK * 、EGAK * 、EGEK * 、EGK * 、EGE[Peg3]-ESK * 、GESESEK * 、GEK * or EK * can be obtained.

[0073] When R1 or R2 is an amino acid of length 1, it can be a D-amino acid, for example, {d}Y.

[0074] R1 and R2 may exist independently or may not exist. There may be cases where it is desirable for R2 to exist. Without wishing to be bound by any particular theory, the presence of R1 and / or R2 is thought to be able to improve the stability of the compound.

[0075] Preferred classes of compstatin analogs and exemplary compounds are further considered below.

[0076] In a further embodiment, the present invention provides a composition comprising a compstatin analog of the present invention, or a pharmaceutically acceptable salt or solvate thereof, mixed with a carrier. Optionally, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.

[0077] In a further aspect, the present invention provides a pharmaceutical composition comprising a compstatin analog of the present invention, or a pharmaceutically acceptable salt or solvate thereof, mixed with a pharmaceutically acceptable carrier, excipient or vehicle.

[0078] In a further embodiment, the present invention provides a compstatin analog of the present invention for use in therapy.

[0079] In a further embodiment, the present invention provides a compstatin analog of the present invention for use in a method of inhibiting complement activation. By way of example, inhibition of complement activation includes one or more biological activities selected from (1) inhibition of binding to C3 protein, (2) inhibition of binding to C3b protein, and / or (3) inhibition of cleavage of native C3 by C3 convertase. Examples of diseases or conditions that can be treated using the compstatin analogs of the present invention are described below.

[0080] In a further embodiment, the present invention provides a compstatin analog of the present invention for use in a method of inhibiting complement activation that occurs during cell or organ transplantation.

[0081] In a further embodiment, the present invention provides a method of inhibiting complement activation for treating a subject in need thereof, the method comprising administering to the subject a compstatin analog of the present invention, thereby inhibiting complement activation in the subject. Examples of diseases or conditions that can be treated using the compstatin analogs of the present invention are described below.

[0082] In a further embodiment, the present invention provides an ex vivo method of inhibiting complement activation in an extracorporeal shunt of a physiological fluid, the method comprising contacting the physiological fluid with a compstatin of the present invention, thereby inhibiting complement activation.

[0083] In a further embodiment, the present invention provides the use of a compstatin analog of the present invention in the preparation of a medicament for inhibiting complement activation. Examples of diseases or conditions that can be treated using the compstatin analogs of the present invention are described below.

[0084] Here, embodiments of the present invention will be described by way of example, but not by way of limitation. BRIEF DESCRIPTION OF THE DRAWINGS

[0085]

Figure 1a

Figure 1b

Figure 1c

Figure 1d

Figure 1e

Figure 1f

Best Mode for Carrying Out the Invention

[0086] As used herein, "and / or" is to be construed as each specific disclosure of two specified features or components, with or without the other. For example, "A and / or B" should be construed as (i) A, (ii) B, and (iii) each specific disclosure of A and B, each being construed as if separately described herein.

[0087] Unless otherwise indicated in the context, the above descriptions and definitions of features are not limited to specific embodiments or forms of the invention, but apply equally to all embodiments and forms described.

[0088] Various publications, including patents, published applications, technical papers, and academic papers, are cited throughout the specification. Each of these cited publications is hereby incorporated by reference in its entirety.

[0089] Unless otherwise defined herein, scientific and technical terms used in this application shall have the meanings commonly understood by those skilled in the art. Generally, the nomenclature and techniques used in connection with chemistry, molecular biology, cell and cancer biology, immunology, microbiology, pharmacology, and protein and nucleic acid chemistry described herein are well-known and commonly used in the art.

[0090] Each embodiment of the invention described herein can be taken alone or in combination with one or more other embodiments of the invention.

[0091] Unless otherwise specified, the following definitions are provided for certain terms used in this specification.

[0092] Definition Throughout this specification, the terms "comprising" and its grammatical variations, such as "comprises" or "comprised of", are understood to mean including the recited integer or component, or group of integers or components, but not excluding other integers or components, or groups of integers or components.

[0093] The singular forms "a", "an", and "the" include the plural unless the context clearly dictates otherwise.

[0094] The term "comprising" is used to mean "including, but not limited to". "Comprising" and "including, but not limited to" can be used interchangeably.

[0095] The terms "patient", "subject", and "individual" can be used interchangeably. A subject can be a human or non-human mammal, such as a non-human primate (e.g., ape, Old World monkey or New World monkey), livestock (e.g., cow or pig), companion animal (e.g., dog or cat), or laboratory animal, such as a rodent (e.g., mouse or rat).

[0096] Throughout this specification and the claims, the conventional three-letter and one-letter codes for the natural amino acids are used. That is, A (Ala), G (Gly), L (Leu), I (Ile), V (Val), F (Phe), W (Trp), S (Ser), T (Thr), Y (Tyr), N (Asn), Q (Gln), D (Asp), E (Glu), K (Lys), R (Arg), H (His), M (Met), C (Cys) and P (Pro), and the generally accepted three-letter codes for other α-amino acids, for example, ornithine (Nle), sarcosine (Sar), α-aminoisobutyric acid (Aib), 2,3-diaminopropanoic acid (Dap), 2,4-diaminobutyric acid (Dab) and 2,5-diaminopentanoic acid (ornithine; Orn), 1-methyl-tryptophan (1-Me-Trp, 1Me-Trp or 1MeTrp), 1-formyl-tryptophan (1-For-Trp or 1For-Trp or 1ForTrp), 1-naphthalan (1-Nal or 1Nal), 2-naphthalan (2-Nal or 2Nal), 5-methyl-tryptophan (5-Me-Trp or 5Me-Trp or 5MeTrp), p-benzoyl-phenylalanine (Bpa) 2-indanylglycine (2Igl or 2-Igl). Other α-amino acids, when used in the general formulas or sequences herein, especially when the residues of the formula or sequence are shown using the one-letter code, may be indicated by square brackets "[]" (e.g., "[Nle]"). Letter codes. The above 20 "naturally occurring" amino acids are those encoded by the standard genetic code and are sometimes referred to as "proteinogenic" amino acids.

[0097] Gamma-Glu and beta-Asp (gamma-Glu) and beta-Asp (beta-Asp), also called gamma-Glu and beta-Asp (or isoglutamic acid and isoaspartic acid), refer to glutamic acid or aspartic acid that participate in peptide bonds via the γ- or β-carboxylic acid (usually regarded as the side-chain carboxyl group), respectively, rather than the conventional stereochemistry. Similarly, εLys or isoLys refers to lysine that participates in peptide bonds via the ε-amino group (usually regarded as the side-chain amino group) rather than the α-amino group.

[0098] β-Ala, also known as beta-Ala, means 3-aminopropanoic acid.

[0099] Peg3 refers to the residue of 8-amino-3,6-dioxaoctanoic acid (also known as {2-[2-aminoethoxy]ethoxy}acetic acid), and Peg4 refers to the residue of 11-amino-3,6,9-trioxaundecanoic acid. The residue can also be represented as [8-amino-3,6-dioxaoctanoyl].

[0100] [Chemical formula]

[0101] Unless otherwise specified, the amino acid residues in the peptides of the present invention are in the L-configuration. However, in some examples, D-configuration amino acids can be incorporated. In this context, amino acid codes written in lowercase represent the D-configuration of the amino acid. For example, "k" represents the D-configuration of lysine (K), or a D-configuration amino acid can be written as (d)X or {d}X, where X is an amino acid. For example, (d)Y or {d}Y represents the D-configuration of tyrosine (Y).

[0102] The cysteine residue indicated by "C(1)" indicates that the side chain is involved in a disulfide bond. Thus, typically, there will be two such residues in any given molecule.

[0103] The terminal groups present at the N-terminus and C-terminus of the peptide backbone are named Y1 and Y2, respectively. Thus, Y1 is bonded to the nitrogen atom of the N-terminal amino group, and Y2 is bonded to the carbonyl carbon atom of the C-terminus.

[0104] Y1 = hydrogen (also shown as "H-" or "Hy-") represents a hydrogen atom corresponding to the presence of a free primary or secondary amino group at the N-terminus. Y1 = acetyl ("Ac") indicates the presence of a secondary acetylamide group at the N-terminus.

[0105] Y2 = "OH" or "NH 2 " indicates the presence of a carboxy (COOH) group or an amide (CONH 2 ) group at the C-terminus of the molecule.

[0106] Either or both of Y1 and Y2 may be a lipophilic group Φ. Typically, only one of Y1 or Y2 is a lipophilic group Φ.

[0107] In some embodiments, regardless of whether the molecule contains a lipophilic group elsewhere, Y2 is NH 2 or OH. In one embodiment, Y1 is hydrogen or acetyl and Y2 is OH or NH 2 .

[0108] In some embodiments, regardless of whether the molecule contains a lipophilic group elsewhere, Y2 is NH 2 . In one embodiment, Y1 is hydrogen or acetyl and Y2 is NH 2 .

[0109] In some embodiments, regardless of whether the molecule contains a lipophilic group elsewhere, Y2 is NH 2 and Y1 is acetyl.

[0110] Various terms related to the methods and other embodiments of the present invention are used throughout the specification and claims. Unless otherwise indicated, such terms are given their ordinary meaning in the art. Other specifically defined terms should be interpreted in a manner consistent with the definitions provided herein. As used herein, the term "about" means, when referring to measurable values such as amounts, time durations, etc., in some embodiments, variations of ±5%, in some embodiments, ±1%, and in some embodiments, ±0.1%, and such variations are suitable for manufacturing and using the disclosed compounds and compositions.

[0111] As used herein, the term "full-length compstatin" refers to a 27-amino acid peptide having the sequence IC(1)VVQDWGHHRC(1)TAGHMANLTSHASAI, where C(1) represents cysteine residues linked by disulfide bonds. As described above, the tridecapeptide Ile 1 -Cys 2 -Val 3 -Val 4 -Gln 5 -Asp 6 -Trp 7 -Gly 8 -His 9 -His 10 -Arg 11 -Cys 12 -Thr 13 -NH 2 is linked by a disulfide bond between the cysteine residues at positions 2 and 12 and is a truncated form of full-length compstatin that retains the activity of the full-length peptide. The N-terminal acetylated version of this tridecapeptide is referred to herein as "Ac-compstatin".

[0112] As used herein, the term "compstatin analog" refers to a modified Ac-compstatin that includes one or more substitutions of natural and non-natural amino acids, or amino acid analogs, as well as various modifications within or between amino acids, as described in more detail herein. Compstatin analogs can include about 1, 2, 3, 4, or 5 amino acid modifications relative to Ac-compstatin. Compstatin analogs can include 5, 6, 7, 8 or more amino acid modifications relative to Ac-compstatin. Compstatin analogs can include about 5, 6, 7, or 8 amino acid modifications relative to Ac-compstatin.

[0113] The term "analogue" is often used with respect to a protein or peptide of interest before further chemical modification (derivatization), particularly acylation. Products resulting from such chemical modification (derivatization) are often referred to as "derivatives" or "acylated analogues". However, in the context of this application, the term "analogue" refers to analogues of Ac-Compstatin, as well as (acylated) derivatives of such Ac-Compstatin analogues.

[0114] When referring to the position of an amino acid or analogue in Ac-Compstatin or a Compstatin analogue, the positions are numbered from 1 (Ile in Compstatin) to 13 (Thr in Compstatin). For example, the Gly residue occupies the "8th position". When used to describe a Compstatin analogue peptide of the present invention, "C(1)" indicates a disulfide bond between each cysteine residue in the Compstatin analogue.

[0115] The terms "pharmaceutically active" and "biologically active" refer to the ability of the compounds of the present invention to bind to C3 or a fragment thereof and inhibit complement activation. The biological activity of Compstatin analogues can be measured by one or more of several technically recognized assays, as described in more detail herein.

[0116] As used herein, "L - amino acid" refers to any of the naturally occurring left - handed α - amino acids normally present in proteins, or alkyl esters of those α - amino acids. The term "D - amino acid" refers to right - handed α - amino acids. Unless otherwise specified, all amino acids referred to herein are L - amino acids.

[0117] "Hydrophobic" or "non - polar" are used synonymously herein and refer to any intermolecular or intramolecular interaction not characterized by a dipole.

[0118] As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by making its acid or base salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Thus, the term "acid addition salt" refers to the corresponding salt derivatives of the parent compound prepared by the addition of an acid. Pharmaceutically acceptable salts include, for example, conventional salts or quaternary ammonium salts of the parent compound formed from inorganic or organic acids. For example, such conventional salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfuric acid, phosphoric acid, nitric acid; and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanyl, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and other organic acids prepared salts, but are not limited thereto. Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compound, including the free acid, free base, and zwitterion, are considered to be within the scope of the present invention.

[0119] Compstatin analog The N-terminal acetylated 13-amino acid peptide Ac-compstatin binds to C3 and is known to prevent cleavage by C3 convertase. Since its discovery by phage display, modifications to the 13-amino acid Ac-compstatin sequence have been made to find analogs with increased biological activity. However, in the core sequence between the two cysteine residues at positions 2 and 12, alanine scan experiments have previously produced analogs showing only a slight improvement in biological activity, and only minor modifications are tolerated. Modifications include changing valine at position 4 to tryptophan or a tryptophan analog, thereby increasing biological activity, and changing histidine at position 9 to alanine or an analog thereof.

[0120] In particular, previous attempts to introduce modifications into the valine residue at position 3 and replace it with glycine, alanine, D-valine or leucine have been shown to result in a decrease in biological activity. In contrast to these prior art findings, the inventors have surprisingly found that the change of valine to isoleucine is well tolerated and provides an improvement in biological activity, as shown in the following examples.

[0121] While not wishing to be bound by any particular theory, the inventors reason that this modification can be combined with the introduction of one or more polar or charged amino acids in the core sequence and can be used as an approach to increase the solubilization ability of the compstatin peptide. Initially, combining glutamic acid or serine at position 9 with valine 3 resulted in a decrease in activity compared to the reference sequence 4W9A. However, when these changes were combined with the introduction of isoleucine at position 3, a surprising increase in biological activity was observed, particularly with respect to the combination of isoleucine at position 3 and glutamic acid at position 9. This finding correlates with an improvement in binding to C3 measured by surface plasmon resonance (SPR) (see Table 7).

[0122] In a further series of experiments to verify these findings, compstatin peptides having glutamic acid at position 9 were combined with different substitutions at position 3 that are normally considered "conservative" substitutions of isoleucine, which also indicates that peptides having isoleucine at position 3 are the most active.

[0123] In summary, these experiments show that substituting the valine residue at position 3 with isoleucine surprisingly provides a compstatin peptide having increased biological activity and improved binding to C3. Furthermore, the experiments surprisingly show that these changes can be readily combined with other modifications in the core sequence of compstatin analogs, and the addition of N- and C-terminal sequences, for example, improvements in the solubility of the compstatin peptide, such as improvements at higher concentrations.

[0124] The introduction of isoleucine instead of valine at the 3-position of a further prior art compound named "Cp40" (Qu et al., Immunobiology 2013, 281(4): 496-505; also referred to as "peptide 14") also increased the binding affinity for C3, as measured by SPR.

[0125] In any embodiment, X1 can be Y, I or F, and in any embodiment, X4 can be W, V, 1-Nal, 2-Nal or 1-Me-Trp. In any embodiment, X6 may be E or D, X9 may be A, E, D, K or S, and in any embodiment, X13 may be T, S, E, I, Sar, K or G. In any embodiment, X13 may be T, I, S, E, K or Sar. In any embodiment, X13 can be T, S, E or Sar.

[0126] Lipophilic substituent Compstatin analogs can have a lipophilic group, denoted as Φ.

[0127] The lipophilic group may be covalently attached to the N-terminus and / or C-terminus of the molecule. Y1 can be Φ (instead of H or Ac), and / or Y2 can be Φ (instead of OH or NH 2 ).

[0128] Additionally or alternatively, the lipophilic group may be covalently linked to the side chain of an amino acid residue within the analog. The residue may be part of R1, R2 of the molecule or part of the Compstatin analog portion X1-X13.

[0129] The lipophilic group Φ typically binds via an acyl group. Thus, the modification is called acylation, but is also called lipidation.

[0130] The lipophilic group is designated as Z herein 1It is referred to as and contains a long-chain alkylene group derived from a fatty acid called a lipophilic substituent. Without wishing to be bound by theory, it is believed that the lipophilic substituent binds to plasma proteins (e.g., albumin) in the bloodstream and thus shields the compounds used in the context of the present invention from enzymatic degradation, thereby enhancing the half-life of the compounds. The lipophilic substituent can also modulate the potency of the compounds.

[0131] Z 1 may be directly attached to the amino acid sequence (including R1 and R2 extensions) or via a spacer Z as defined herein. 2 via.

[0132] In other words, Φ is Z 1 - or Z 1 -Z 2 - may be.

[0133] When Y1 is Φ, Φ is preferably Z 1 -.

[0134] When the lipophilic group Φ is attached to an amino acid side chain (i.e., Y1 is hydrogen or Ac), Φ is preferably Z 1 -Z 2 - may be.

[0135] In certain embodiments, only one amino acid side chain is attached to the lipophilic substituent. In other embodiments, two amino acid side chains are each conjugated to a lipophilic substituent. In still further embodiments, three or more amino acid side chains are each conjugated to a lipophilic substituent. When the compound contains two or more lipophilic substituents, they may be the same or different substituents.

[0136] In certain embodiments, only one lipophilic group Φ is present in the molecule.

[0137] The term "conjugated", as used herein, describes the covalent attachment of one identifiable chemical moiety to another and the structural relationship between such moieties. It should not be construed to mean a particular synthetic method. One or more spacers Z 2 , if present, are used to provide a spacing between the compound and the lipophilic substituent Z 1 .

[0138] The lipophilic substituent can be attached to the N-terminal nitrogen, or to an amino acid side chain, or to the spacer via an ester, sulfonyl ester, thioester, amide or sulfonamide. Thus, it will be understood that the lipophilic substituent can contain an acyl group, a sulfonyl group, an N atom, an O atom or an S atom that forms part of an ester, sulfonyl ester, thioester, amide or sulfonamide.

[0139] Preferably, the acyl group in the lipophilic substituent forms part of an amide or ester having an N-terminal nitrogen, or an amino acid side chain, or a spacer. The lipophilic substituent can include a hydrocarbon chain having 10 to 24 carbon (C) atoms, such as 10 to 22 C atoms, such as 10 to 20 C atoms. Preferably, it has at least 11 C atoms and preferably has 18 or fewer C atoms. For example, the hydrocarbon chain can contain 12, 13, 14, 15, 16, 17 or 18 carbon atoms. The hydrocarbon chain can be linear or branched and can be saturated or unsaturated.

[0140] The hydrocarbon chain can incorporate a phenylene or piperazinylene moiety in its length, as shown, for example, below (where - represents a point of attachment within the chain). These groups should be "counted" as 4 carbon atoms in the length of the chain.

[0141]

Chemical Structure

[0142] From the above considerations, it will be understood that the hydrocarbon chain can be substituted at the part forming a part of the bond to the amino acid side chain or the spacer, such as an acyl group, a sulfonyl group, an N atom, an O atom or an S atom. Most preferably, the hydrocarbon chain is substituted with an acyl group, and thus the hydrocarbon chain may be part of an alkanoyl group, such as dodecanoyl, 2-butyloctanoyl, tetradecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl or eicosanoyl group. Alternatively, Z 1 group is derived from a long-chain saturated α,ω-dicarboxylic acid of the formula HOOC-(CH 2 ) 12-22 -COOH, preferably a long-chain saturated α,ω-dicarboxylic acid having an even number of carbon atoms in the aliphatic chain.

[0143] In other words, Z 1 can be A-C 12-22 alkylene-(CO)-, where A can be H or COOH, where the alkylene can be straight-chain or branched-chain, saturated or unsaturated, and optionally, a phenylene or piperazinylene moiety can be incorporated into its length.

[0144] For example, Z 1 can be the following. Dodecanoyl, i.e., H-(CH 2 ) 11 -(CO)-; Tetradecanoyl, i.e., H-(CH 2 ) 13 -(CO)-; Hexadecanoyl, i.e., H-(CH 2 ) 15 -(CO)-; 13-Carboxytridecanoyl, i.e., HOOC-(CH 2 ) 12 -(CO)-; 15-Carboxypentadecanoyl, i.e., HOOC-(CH 2 ) 14 -(CO)-; 17-Carboxyheptadecanoyl, i.e., HOOC-(CH 2 ) 16-(CO)-; 19-carboxynonadecanoyl, i.e., HOOC-(CH 2 ) 18 -(CO)- or 21-carboxyphenicosanoyl, i.e., HOOC-(CH2) 20 -(CO)-.

[0145] When a carboxylic acid is present, it may be replaced with a biotar, phosphoric acid, or sulfonic acid. Biotars suitable for carboxylic acids are known in the art and include tetrazole, acylsulfonamide, acylhydroxylamine, and squaric acid derivatives.

[0146] As described above, the lipophilic substituent Z 1 can be conjugated to the amino acid side chain or the N-terminal nitrogen by one or more spacers Z 2 .

[0147] When present, the spacer is attached to the lipophilic substituent and the amino acid side chain or the N-terminal nitrogen. The spacer can be attached independently to the lipophilic substituent and the amino acid side chain by an ester, sulfonyl ester, thioester, amide, or sulfonamide. Thus, it can contain two moieties independently selected from an acyl, sulfonyl, N atom, O atom, or S atom. The spacer may be composed of a linear C 1-10 hydrocarbon chain, or more preferably a linear C1-5 hydrocarbon chain. Further, the spacer may be substituted with one or more substituents selected from C 1-6 alkyl, C 1-6 alkylamine, C 1-6 alkylhydroxy, and C 1-6 alkylcarboxy.

[0148] The spacer can be, for example, a residue of any natural or non-natural amino acid. For example, the spacer can be a residue of Gly, Pro, Val, Leu, Ile, Met, Cys, Phe, Tyr, Trp, His, Lys, Arg, Gln, Asn, Glu, Asp, γ-Glu, β-Asp, ε-Lys, Asp, Ser, Thr, Dapa, Gaba, Aib, β-Ala (i.e., 3-aminopropanoyl), 4-aminobutanoyl, 5-aminohexanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoanoyl, 8-amino-3,6-dioxaoctanoyl. In certain embodiments, the spacer is a residue of Glu, γ-Glu, ε-Lys, β-Ala (i.e., 3-aminopropanoyl), 4-aminobutanoyl, 8-aminooctanoyl or 8-amino-3,6-dioxaoctanoyl (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazin-1-yl)-carboxylic acid. In the present invention, γGlu and isoGlu are used interchangeably.

[0149] Z 2 is preferably a sequence of 1 to 6 residues of a compound selected from γGlu, βAsp, D, E, K, Orn, S, T, A, βAla, G, P, V, V, L, I, Y, Q, N, Dapa, Gab, or Aib, or their corresponding D-forms, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanonyl, 9-aminononanoyl, and 10-aminodecanoyl, 8-amino-3,6-dioxaoctanoic acid (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazin-1-yl)-carboxylic acid.

[0150] For example, Z 2 can be or can include: [γGlu]; [γGlu][Peg3][Peg3]-; [(piperazin-1-yl)-acetyl][Peg3][Peg3]; [γGlu]-G-[γGlu]; [γGlu]-K-[γGlu]; [γGlu]-KG-[γGlu]; or [γGlu]-G-[Peg3][γGlu][Peg3].

[0151] Z 2 is suitably attached on each side by an amide bond. Other suitable bonds with appropriate atomic substitutions can be used, for example, sulfinamide, sulfonamide, or ester bonds, or amino, ether, or thioether bonds are conceivable.

[0152] In other words, in some embodiments, the lipophilic group Φ is Z 1 - or Z 1 -Z 2 -, where Z 1 is A-C 12-22 alkylene-(CO)-; A is H or COOH, alkylene can be straight or branched, and can be saturated or unsaturated, and can optionally incorporate a phenylene or piperazinylene moiety along its length; Z 2 is a sequence of 1 to 6 residues of a compound selected from γ-Glu, βAsp, D, E, K, Orn, S, T, A, β-Ala, G, P, V, V, L, I, Y, Q, N, Dapa, Gab, or Aib, or their corresponding D-forms, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanonyl, 9-aminononanoyl, and 10-aminodecanoyl, 8-amino-3,6-dioxaoctanoic acid (Peg3), 11-amino-3,6,9-trioxaundecanoic acid (Peg4) or (piperazin-1-yl)-carboxylic acid, for example, a linker sequence selected from the following: [Glu], [γGlu][Peg3][Peg3]-; [(piperazin-1-yl)-acetyl][Peg3][Peg3]; [γGlu]-G-[γGlu]; [γGlu]-K-[γGlu]; [γGlu]-KG-[γGlu]; and [γGlu]-G-[Peg3][γGlu][Peg3].

[0153] The amino acid side chain to which the lipophilic substituent is conjugated typically contains a carboxy, hydroxyl, thiol, amide or amine group for forming an ester, sulfonyl ester, thioester, amide or sulfonamide with a spacer or lipophilic substituent. An amide bond is particularly preferred, and thus the amino acid may be any amino acid having an amine group in its side chain, although it is obvious that side chains having other functional groups are conceivable. Thus, the amino acid side chain can be the side chain of a Glu, Lys, Ser, Cys, Dbu, Dpr or Orn residue. For example, it may be the side chain of a Lys, Glu or Cys residue. When two or more side chains have lipophilic substituents, they can be independently selected from their residues.

[0154] Typically, the amino acid side chain is the side chain of a Lys residue.

[0155] Lipophilic moiety Z 1 and spacer Z 2 Examples of lipophilic substituents containing are shown in the following formula.

[0156]

Chemical formula

[0157] Here, the side chain of the Lys residue is covalently bonded via an amide bond to the γGlu spacer (Z 2 ). The hexadecanoyl group (Z 1) is covalently linked to the γGlu spacer via an amide bond. This combination of the lipophilic moiety conjugated to the Lys residue and the spacer can be referred to, for example, by the short notation K(hexadecanoyl-γGlu) when represented by the formula of a particular compound. γGlu is also called isoglutamic acid, and the hexadecanoyl group is called the palmitoyl group. Thus, it will be apparent that the notation (hexadecanoyl-γGlu) is equivalent to the notation (isoGlu(Palm)) or (isoGlu(palmitoyl)) used, for example, in PCT / GB2008 / 004121.

[0158] Another Z 1 group is derived from a long-chain saturated α,ω-dicarboxylic acid of the formula HOOC-(CH 2 ) 12-22 -COOH as exemplified below.

[0159]

Chemical formula

[0160] Here, the side chain of the Lys residue is covalently bonded to the γGlu spacer (Z 2 ). The 15-carboxypentadecanoyl group (Z 1 ) is covalently bonded to the γGlu spacer via an amide bond, and this combination of the lipophilic moiety attached to the Lys residue and the spacer can be referred to, for example, by the short notation K(15-carboxypentadecanoyl-γ-Glu) when represented by the formula of a particular compound. γGlu is also called isoglutamic acid.

[0161] Certain preferred Φ groups (Z 1 - and Z 1 -Z 2 -) include the following: [15-carboxy-pentadecanoyl]; [15-carboxy-pentadecanoyl][γGlu], [15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3]; [19-Carboxy-nonadecanoyl][γGlu][Peg3][Peg3]; [15-Carboxy-pentadecanoyl][(piperazin-1-yl)-acetyl][Peg3]; [17-Carboxy-heptadecanoyl][γGlu]G[γGlu]; [17-Carboxy-heptadecanoyl][γGlu]K[γGlu]; [17-Carboxy-heptadecanoyl][γGlu]KG[γGlu]; [17-Carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu][Peg3]; [15-Carboxy-pentadecanoyl][γGlu]G[γGlu]; [17-Carboxy-heptadecanoyl]; [17-Carboxy-heptadecanoyl][γGlu] [19-Carboxy-nonadecanoyl][γGlu]G[γGlu]; and [17-Carboxy-heptadecanoyl][γGlu][Peg3][Peg3].

[0162] Examples of the Φ group (Z 1 - and Z 1 -Z 2 -) are shown below. The wavy lines indicate the bonds to the peptide (amino acid side chain, N-terminal nitrogen, or C-terminal carbon).

[0163]

Chemical Structure

[0164]

Chemical Structure

[0165]

Chemical Structure

[0166]

Chemical Structure

[0167] [Chemical]

[0168] [Chemical]

[0169] [Chemical]

[0170] [Chemical]

[0171] [Chemical]

[0172] [Chemical]

[0173] One skilled in the art will be well aware of the appropriate techniques for preparing the compounds used in the context of the present invention. For examples of appropriate chemistry, see WO98 / 08871, WO00 / 55184, WO00 / 55119, Madsen et al., J. Med. Chem. 50:6126-32 (2007) and Knudsen et al., J. Med Chem. 43:1664-1669 (2000), which are hereby incorporated by reference.

[0174] In some embodiments, the compstatin analog has the above-described lipophilic group Φ attached to an amino acid at one or more positions corresponding to positions 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 13 of the compstatin-like sequence, i.e., positions X1-X13.

[0175] In certain embodiments, the compstatin analog has a lipophilic substituent as described above attached to an amino acid at one or more positions corresponding to positions X1, X11, or X13, or to an amino acid within R1 or R2, or to the N-terminus as the Y1 group.

[0176] Well-established conjugation strategies have been developed for C-terminal acylation or lipidation of peptides. For example, such conjugation can be carried out by click chemistry (i.e., a bioorthogonal azide-alkyne conjugation reaction catalyzed by Cu(I)), or by other conjugation strategies known to those skilled in peptide chemistry.

[0177] The compstatin analog may comprise one of the following sequences: IC(1)IWQDWGAHRC(1)T IC(1)IWQDWGEHRC(1)T ESSAIC(1)IWQDWGEHRC(1)T IC(1)I[1MeTrp]QDWGEHRC(1)T IC(1)IWQDWGKHRC(1)T IC(1)IWQDWGSHRC(1)T IC(1)IWQKWGEHRC(1)T IC(1)IWQKWGAHRC(1)TGAES YC(1)IWQDWGEHRC(1)T ESSAYC(1)IWQDWGEHRC(1)T [Sar]C(1)IWQDWGEHRC(1)T IC(1)IWQDWGAHRC(1)E IC(1)IWQDWGEHRC(1)[Sar] ESSAIC(1)IWQDWGEHRC(1)TGAES IC(1)IWQDWGEHRC(1)TGAES IC(1)IWQEWGEHRC(1)T IC(1)IWQDWGDHRC(1)T IC(1)IWQDWGRHRC(1)T IC(1)IWQDWGAHSC(1)T IC(1)IWQDWGEHSC(1)T IC(1)IWQDWGEHRC(1)S IC(1)IWQDWGEHRC(1)E FC(1)IWQDWGEHRC(1)T IC(1)IWQDWGEHRC(1)TEGE IC(1)IWQDWGEHRC(1)TEA IC(1)IWQDWGEHRC(1)TE IC(1)IWQDWGEHRC(1)EGE EGSAIC(1)IWQDWGEHRC(1)[Sar]E EGSAIC(1)IWQDWGEHRC(1)T EGEIC(1)IWQDWGEHRC(1)T ESEIC(1)IWQDWGEHRC(1)T

[0178] SEIC(1)IWQDWGEHRC(1)TEA EIC(1)IWQDWGEHRC(1)TE EIC(1)IWQDWGEHRC(1)TEGE EGEIC(1)IWQDWGEHRC(1)EGE ESEIC(1)IWQDWGEHRC(1)EGE KEKIC(1)IWQDWGEHRC(1)TEKE EKGIC(1)IWQDWGEHRC(1)TEKP IC(1)IWQDWGEHRC(1)TEGK GSAIC(1)IWQDWGEHRC(1)[Sar]E SAIC(1)IWQDWGEHRC(1)[Sar]E SAIC(1)IWQDWGEHRC(1)TEG FC(1)IWQDWGEHRC(1)TGAE EGSAIC(1)IWQDWGEHRC(1)[Sar]EGE EGSAFC(1)IWQDWGEHRC(1)[Sar]E ESSAIC(1)IWQDWGAHRC(1)T IC(1)IWQDWGAHRC(1)TGAES {d}YIC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)-[N-Me-Ile] EGSAIC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E EGSAIC(1)I[2-Nal]QDWGEHRC(1)[Sar]E IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES IC(1)I[2-Nal]QDWGEHRC(1)TGAES EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E EGSAIC(1)IWQDWGEHRC(1)TE EGSAFC(1)I[1-Nal]QDWGEHRC(1)TE EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)TE EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)TE EGSAFC(1)I[2-Nal]QDWGEHRC(1)TE FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES FC(1)I[1-Nal]QDWGEHRC(1)TGAES FC(1)I[2-Nal]QDWGEHRC(1)TGAES YC(1)I[2-Nal]QDWGEHRC(1)TGAES YC(1)IWQDWGEHRC(1)TGAES

[0179] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES {d}YFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]EA SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TEA SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA SEFC(1)I[1-Me-Trp]QDWGEHRC(1)SEA EFC(1)I[1-Me-Trp]QDWGEHRC(1)ES SEFC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]EA GEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA GE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA SE[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)TEA SE[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA {d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA。

[0180] For example, the complestatin analogs can be as follows: Ac-IC(1)IWQDWGAHRC(1)T-NH2 (Compound 1) Ac-IC(1)IWQDWGEHRC(1)T-NH2 (Compound 2) Ac-ESSAIC(1)IWQDWGEHRC(1)T-NH2 (Compound 3) Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)T-NH2 (Compound 4) Ac-IC(1)IWQDWGKHRC(1)T-NH2 (Compound 5) Ac-IC(1)IWQDWGSHRC(1)T-NH2 (Compound 6) Ac-IC(1)IWQKWGEHRC(1)T-NH2 (Compound 7) Ac-IC(1)IWQKWGAHRC(1)TGAES-NH2 (Compound 8) Ac-YC(1)IWQDWGEHRC(1)T-NH2 (Compound 9) Ac-ESSAYC(1)IWQDWGEHRC(1)T-NH2 (Compound 10) Ac-[Sar]C(1)IWQDWGEHRC(1)T-NH2 (Compound 11) Ac-IC(1)IWQDWGAHRC(1)E-NH2 (Compound 12) Ac-IC(1)IWQDWGEHRC(1)[Sar]-NH2 (Compound 13) Ac-ESSAIC(1)IWQDWGEHRC(1)TGAES-NH2 (Compound 14) Ac-IC(1)IWQDWGEHRC(1)TGAES-NH2 (Compound 15) Ac-IC(1)IWQEWGEHRC(1)T-NH2 (Compound 16) Ac-IC(1)IWQDWGDHRC(1)T-NH2 (Compound 17) Ac-IC(1)IWQDWGRHRC(1)T-NH2 (Compound 18) Ac-IC(1)IWQDWGAHSC(1)T-NH2 (Compound 19) Ac-IC(1)IWQDWGEHSC(1)T-NH2 (Compound 20)

[0181] Ac-IC(1)IWQDWGEHRC(1)S-NH2 (Compound 21) Ac-IC(1)IWQDWGEHRC(1)E-NH2 (Compound 22) Ac-FC(1)IWQDWGEHRC(1)T-NH2 (Compound 23) Ac-IC(1)IWQDWGEHRC(1)TEGE-NH2 (Compound 24) Ac-IC(1)IWQDWGEHRC(1)TEA-NH2 (Compound 25) Ac-IC(1)IWQDWGEHRC(1)TE-NH2 (Compound 26) Ac-IC(1)IWQDWGEHRC(1)EGE-NH2 (Compound 27) Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2 (Compound 28) Ac-EGSAIC(1)IWQDWGEHRC(1)T-NH2 (Compound 29) Ac-EGEIC(1)IWQDWGEHRC(1)T-NH2 (Compound 30) Ac-ESEIC(1)IWQDWGEHRC(1)T-NH2 (Compound 31) Ac-SEIC(1)IWQDWGEHRC(1)TEA-NH2 (Compound 32) Ac-EIC(1)IWQDWGEHRC(1)TE-NH2 (Compound 33) Ac-EIC(1)IWQDWGEHRC(1)TEGE-NH2 (Compound 34) Ac-EGEIC(1)IWQDWGEHRC(1)EGE-NH2 (Compound 35) Ac-ESEIC(1)IWQDWGEHRC(1)EGE-NH2 (Compound 36) Ac-KEKIC(1)IWQDWGEHRC(1)TEKE-NH2 (Compound 37) Ac-EKGIC(1)IWQDWGEHRC(1)TEKP-NH2 (Compound 38) Ac-IC(1)IWQDWGEHRC(1)TEGK-NH2 (Compound 39) Ac-GSAIC(1)IWQDWGEHRC(1)[Sar]E-NH2 (Compound 40)

[0182] Ac-SAIC(1)IWQDWGEHRC(1)[Sar]E-NH2 (Compound 41) Ac-SAIC(1)IWQDWGEHRC(1)TEG-NH2 (Compound 42) Ac-FC(1)IWQDWGEHRC(1)TGAE-NH2 (Compound 43) Ac-EGSAIC(1)IWQDWGEHRC(1)[Sar]EGE-NH2 (Compound 44) Ac-EGSAFC(1)IWQDWGEHRC(1)[Sar]E-NH2 (Compound 45) Ac-ESSAIC(1)IWQDWGAHRC(1)T-NH2 (Compound 46) Ac-IC(1)IWQDWGAHRC(1)TGAES-NH2 (Compound 47) H-{d}YIC(1)I[1-Me-Trp]QDW[Sar]AHRC(1)[N-Me-Ile]-NH2 (Compound 48) Ac-EGSAIC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 49) Ac-EGSAIC(1)I[2-Nal]QDWGEHRC(1)[Sar]E-NH2 (Compound 50) Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 51) Ac-IC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 52) Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 53) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 54) Ac-EGSAIC(1)IWQDWGEHRC(1)TE-NH2 (Compound 55) Ac-EGSAFC(1)I[1-Nal]QDWGEHRC(1)TE-NH2 (Compound 56) Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 57) Ac-EGSAFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-NH2 (Compound 58) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)TE-NH2 (Compound 59) Ac-EGSAFC(1)I[2-Nal]QDWGEHRC(1)TE-NH2 (Compound 60)

[0183] Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 61) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 62) Ac-FC(1)I[1-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 63) Ac-FC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 64) Ac-YC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH2 (Compound 65) Ac-YC(1)IWQDWGEHRC(1)TGAES-NH2 (Compound 66) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH2 (Compound 67) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS-NH2 (Compound 68) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA-NH2 (Compound 69) Ac-EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E-NH2 (Compound 70) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 71) Ac-FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 72) H-{d}YFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH2 (Compound 73) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES-NH2 (Compound 74) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 75) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]EA-NH2 (Compound 76) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TEA-NH2 (Compound 77) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH2 (Compound 78) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E-NH2 (Compound 79) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 80)

[0184] Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 81) Ac-SE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 82) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 83) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)SEA-NH2 (Compound 84) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)ES-NH2 (Compound 85) Ac-SEFC(1)I[1-Me-Trp]QDWGEHKC(1)[Sar]EA-NH2 (Compound 86) Ac-GEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA-NH2 (Compound 87) Ac-GE[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 88) Ac-SE[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHRC(1)TEA-NH2 (Compound 89) Ac-SE[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH2 (Compound 90) H-{d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH2 (Compound 91).

[0185] Alternatively, a Compstatin analog may comprise one of the following sequences: [K * GSAIC(1)IWQDWGEHRC(1)TEGE (Compound 100) ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * (Compound 113) EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-[K * (Compound 134) EGSAIC(1)IWQDWGEHRC(1)TEG[K * (Compound 101) EGSAYC(1)I[1-Me-Trp]QDWGEH[K * C(1)[Sar]E (Compound 103) EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-[K * (Compound 104) EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * (Compound 109) EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-[K * (Compound 110) EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]-[K * (Compound 111) FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K * (Compound 102) IC(1)IWQDWGEHRC(1)TEG-[K * (Compound 92) IC(1)IWQDWGEHRC(1)TEGE-[K * (Compound 94) SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-[K * (Compound 105) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K * (Compound 119) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * (Compound 123) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-[K * (Compound 129)

[0186] SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-[K * (Compound 138) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-[K * (Compound 140) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * (Compound 127) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-[K * (Compound 139) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-[K * (Compound 132) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-[K * (Compound 136) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]E-[K * (Compound 137) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-[K * (Compound 130) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-[K * (Compound 142) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-[K * (Compound 126) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-[K * (Compound 133) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K * (Compound 135) SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K * (Compound 120) SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * (Compound 124) SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K * (Compound 112) SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * (Compound 117) SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * (Compound 114)

[0187] SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]A-[K * (Compound 121) SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K * (Compound 122) SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * (Compound 125) EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E(Compound 107) ESSAIC(1)IWQDWGEHRC(1)TEGE(Compound 99) SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3][Peg3]-[K * (Compound 143) SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-[K * (Compound 144) EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-[K * (Compound 145).

[0188] For example, a Compstatin analog may contain one of the following sequences: Ac-[K * GSAIC(1)IWQDWGEHRC(1)TEGE-NH 2 (Compound 100) Ac-ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * -NH 2 (Compound 113) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-[K * -NH 2 (Compound 134) Ac-EGSAIC(1)IWQDWGEHRC(1)TEG-[K * -NH 2 (Compound 101) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEH[K * C(1)[Sar]E-NH 2 (Compound 103) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-[K * -NH 2 (Compound 104) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * -NH 2 (Compound 109) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-[K * -NH 2 (Compound 110) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]-[K * -NH 2 (Compound 111) Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K * -NH 2 (Compound 102)

[0189] Ac-IC(1)IWQDWGEHRC(1)TEG-[K * -NH 2 (Compounds 92, 93, 95, 96, 98) Ac-IC(1)IWQDWGEHRC(1)TEGE-[K * -NH2 (Compound 94, 97) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-[K * -NH 2 (Compound 105, 106) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K * -NH 2 (Compound 119) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * -NH 2 (Compound 123) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-[K * -NH 2 (Compound 129) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-[K * -NH 2 (Compound 138) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-[K * -NH 2 (Compound 140) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * -NH 2 (Compound 127, 128) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-[K * -NH 2 (Compound 139, 141) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-[K * -NH 2 (Compound 132) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-[K* -NH 2 (Compound 136) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]E-[K * -NH 2 (Compound 137) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-[K * -NH 2 (Compounds 130, 131) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE-[Peg3]ES-[K * -NH 2 (Compound 142) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE-[Peg3][Peg3]-[K * -NH 2 (Compound 126) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-[K * -NH 2 (Compound 133)

[0190] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-[K * -NH 2 (Compound 135) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K * -NH 2 (Compound 120) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * -NH 2 (Compound 124) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-[K * -NH 2 (Compounds 112, 118) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * -NH 2 (Compound 117) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-[K * -NH 2 (Compounds 114, 115, 116) Ac-SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]A-[K * -NH 2 (Compound 121) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-[K * -NH 2 (Compound 122) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K * -NH 2 (Compound 125) Φ-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH 2 (Compounds 107, 108) Φ-ESSAIC(1)IWQDWGEHRC(1)TEGE-NH 2 (Compound 99) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3][Peg3]-[K * -NH 2 (Compound 143) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-[K * -NH 2 (Compound 144) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-[K * -NH 2 (Compound 145).

[0191] For example, the compstatin analogs can be the following: Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH 2 (Compound 92) Ac-IC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 93) Ac-IC(1)IWQDWGEHRC(1)TEGE-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 94) Ac-IC(1)IWQDWGEHRC(1)TEG-K((15-carboxy-pentadecanoyl)-[(piperazin-1-yl)-acetyl][Peg3][Peg3])-NH 2 (Compound 95) Ac-IC(1)IWQDWGEHRC(1)TEG-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 96) Ac-IC(1)IWQDWGEHRC(1)TEGE-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 97) Ac-IC(1)IWQDWGEHRC(1)TEG-K([19-carboxy-nonadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 98) [15-carboxy-pentadecanoyl]-ESSAIC(1)IWQDWGEHRC(1)TEGE-NH 2 (Compound 99) Ac-[K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])]-GSAIC(1)IWQDWGEHRC(1)TEGE-NH 2 (Compound 100)

[0192] Ac-EGSAIC(1)IWQDWGEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH 2 (Compound 101) Ac-FC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 102) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEH-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-C(1)[Sar]E-NH 2 (Compound 103) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH 2 (Compound 104) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-K([17-carboxy-heptadecanoyl][γGlu]KG[γGlu])-NH 2 (Compound 105) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 106) [15-carboxy-pentadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH 2 (Compound 107) [17-carboxy-heptadecanoyl]-EGSEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-NH 2 (Compound 108) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 109) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 110) Ac-EGSAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK([γGlu]-K([17-carboxy-heptadecanoyl][γGlu](peg3)(peg3))-NH 2 (Compound 111) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 112) Ac-ASGEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 113)

[0193] Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 114) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 115) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-K[γGlu])-NH 2 (Compound 116) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 117) Ac-SEYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH 2 (Compound 118) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl-][γGlu]G[Peg3][γGlu][Peg3])-NH 2 (Compound 119) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH 2 (Compound 120) Ac-SEYC(1)I[1-Me-Trp]QEW[Sar]EHRC(1)[Sar]EK[γGlu]A-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH 2 (Compound 121) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl]-[γGlu]G[Peg3][γGlu][Peg3])-NH 2 (Compound 122)

[0194] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 123) Ac-SEFC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3[Peg3]-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 124) Ac-SEYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 125) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl)[γGlu]G[γGlu]])-NH 2 (Compound 126) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]-EGE-[Peg3][Peg3]-K([15-carboxy-pentadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 127) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([19-carboxy-nonadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 128) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 129) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 130) Ac-SEFC(1)I[1-Me-Trp]-QDWGEHRC(1)TEGEGGG-K([15-carboxy-pentadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 131) Ac-SEFC(1)I[1-Me-Trp]-QDWGEHRC(1)[Sar]EK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 132) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 133) Ac-EFC(1)I[1-Me-Trp]QDWGEHRC(1)EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 134)

[0195] Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-hexadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 135) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH 2 (Compound 136) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[8-aminooctanoyl]E-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu]])-NH 2 (Compound 137) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 138) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 139) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]ES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH 2 (Compound 140) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGESES-K([17-carboxy-heptadecanoyl][γGlu])-NH 2 (Compound 141) Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu])-NH 2 (Compound 142) Ac-SEFC(1)I[1-Me-Trp]QDWGEHR[C(1)[Sar]EGE[Peg3][Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 143) Ac-SEFC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)[Sar]E[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 144) Ac-EF[C(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EA[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH 2 (Compound 145).

[0196] Compstatin analogs produced by prior art have been shown to have improved activities up to about 99-fold (Mallik, B. et al, 2005, supra; WO2004 / 026328), and up to about 264 (Katragadda et al., 2006, supra; WO2007 / 062249), compared to the parent peptide.

[0197] According to the present invention, information regarding the biological and physicochemical properties of Ac-compstatin bound to C3 has been used to design compstatin analogs having significantly improved activities compared to the parent compstatin analogs.

[0198] Preferably, the compstatin analog has greater activity than Ac-compstatin, for example, at least 10-fold higher activity, at least 20-fold higher activity, at least 30-fold higher activity than Ac-compstatin. In other embodiments, the analog has at least 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150-fold or more activity than Ac-compstatin as compared to when using the assays described in the examples.

[0199] The compounds of the present invention generally have greater activity than other compounds identical in other respects but having valine instead of isoleucine at the position corresponding to Val3 of compstatin.

[0200] Compstatin analogs can bind to C3 and / or C3b and can be activated by inhibiting the activation of the complement cascade, particularly downstream of C3, for example, by inhibiting the cleavage of C3 by C3 convertase.

[0201] Compstatin analogs can also typically inhibit complement-driven hemolysis. Complement-induced hemolysis is typically evaluated (in a "hemolysis assay") by contacting serum from a first mammalian species (e.g., human serum) with erythrocytes (red blood cells; RBCs) from a second mammalian species (e.g., sheep or other suitable species), typically in the presence of mammalian immunoglobulins that can bind to the erythrocytes. Complement in the serum is activated by cell-bound immunoglobulins, causing hemolysis of the erythrocytes, i.e., hemolysis. The immunoglobulins may be from the first species or, as long as they can activate complement from the first species, may be from a third mammalian species.

[0202] In such assays, the test compound is typically pre-incubated with the serum before the serum contacts the erythrocytes. The erythrocytes may also be pre-incubated with the immunoglobulins before contacting the serum.

[0203] In the following examples, human serum is pre-incubated with a test compound, and sheep red blood cells are pre-incubated with rabbit anti-serum against sheep red blood cells before combining the serum and red blood cells.

[0204] Thus, the activity of a Compstatin analog can be determined in relation to one or more biological activities selected from (1) binding to C3 protein, (2) binding to C3b protein, (3) inhibition of cleavage of native C3 by C3 convertase, and (4) inhibition of activation of the complement system.

[0205] Thus, the Compstatin analogs of the present invention can bind to C3 or C3b with higher affinity than Compstatin. For example, they can have a Kd that is at least 10-fold lower, at least 20-fold lower, or at least 30-fold lower than that of Ac-Compstatin, for example, at least 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, or 150-fold lower than that of Ac-Compstatin. The Kd can be determined by surface plasmon resonance (SPR), for example, using the assay described in Example 4.

[0206] The Compstatin analogs of the present invention typically bind to C3 or C3b with higher affinity (i.e., lower Kd) than compounds that are identical in other respects but have valine instead of isoleucine at the position corresponding to Val3 of Compstatin.

[0207] The Compstatin analogs of the present invention may have a higher ability to inhibit hemolysis than Ac-Compstatin. For example, it can inhibit hemolysis with an IC50 that is at least 10-fold lower, at least 20-fold lower, or at least 30-fold lower than that of Ac-Compstatin, such as at least 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 250, 300, 350, 400, 450, 500-fold lower than that of Ac-Compstatin.

[0208] The compstatin analogs of the present invention generally have a higher ability to inhibit hemolysis (i.e., a lower IC 50 ) than other compounds that are identical in other respects but have valine instead of isoleucine at the position corresponding to Val3 of compstatin.

[0209] Preferably, the in vitro effects of the compounds of the present invention are evaluated by measuring their inhibitory effects on the classical complement pathway in a hemolysis assay, for example using the assay described in Example 2.

[0210] Compstatin analogs having acylation may have a lower absolute activity than other compounds that are identical in other respects but lack acylation, but have the additional advantage of an extended in vivo half-life that can offset the apparent decrease in absolute activity.

[0211] Synthesis of compstatin analog It is preferred to synthesize the compstatin analogs of the present invention by solid-phase or liquid-phase peptide synthesis methods. In this context, reference is made to WO98 / 11125, and in particular, Fields, G.B. et al., 2002, “Principles and practice of solid-phase peptide synthesis”. In: Synthetic Peptides (2nd Edition) and the examples of this specification.

[0212] According to the present invention, the compstatin analogs of the present invention can be synthesized or manufactured in many ways, including, for example, methods comprising: (a) synthesizing the compstatin analog by solid-phase or liquid-phase peptide synthesis and recovering the resulting compstatin analog; or (b) expressing the precursor peptide sequence from a nucleic acid construct encoding the precursor peptide, recovering the expression product, and modifying the precursor peptide to obtain the compound of the present invention.

[0213] The precursor peptide can be modified, for example, by introduction of one or more non-proteinogenic amino acids, such as Aib, Orn, Dap, 1-Me-Trp, 1-Nal, 2-Nal, Sar, γGlu or Dab, or by introduction of suitable terminal groups Y1 and / or Y2.

[0214] Expression is typically carried out from a nucleic acid encoding the precursor peptide, which can be carried out in a cell or a cell-free expression system containing such a nucleic acid.

[0215] It is preferred to synthesize the analogs of the invention by solid-phase or liquid-phase peptide synthesis. In this context, reference is made to WO98 / 11125, and in particular, Fields, GB et al., 2002, “Principles and practice of solid-phase peptide synthesis”. In: Synthetic Peptides (2nd Edition) and the examples herein.

[0216] For recombinant expression, a nucleic acid fragment encoding the precursor peptide is inserted into a suitable vector to form a cloning vector or an expression vector. The vector can be in the form of a plasmid, phage, cosmid, mini-chromosome, or virus, depending on the purpose and type of application, but naked DNA that is expressed only transiently in a particular cell is also an important vector. Preferred cloning and expression vectors (plasmid vectors) are capable of autonomous replication, thereby allowing a high copy number for the purpose of high-level expression or high-level replication and allowing subsequent cloning.

[0217] Generally speaking, an expression vector contains the following features in a functional linkage in the 5'→3' direction: a promoter for inducing the expression of a nucleic acid fragment, optionally a nucleic acid sequence encoding a leader peptide that enables secretion (into the extracellular phase or, where applicable, into plasma), a nucleic acid fragment encoding a precursor peptide, and optionally a nucleic acid sequence encoding a terminator. They may contain additional features such as a selection marker and an origin of replication. When operating with an expression vector in a production strain or cell line, it is preferred that the vector can be integrated into the host cell genome. Those skilled in the art are very familiar with suitable vectors and can design one according to their specific requirements.

[0218] The vector of the present invention is used to transform a host cell to produce a precursor peptide. Such transformed cells can be used for the growth of the nucleic acid fragment and the vector, and / or for the recombinant production of the precursor peptide.

[0219] Preferred transformed cells are microorganisms such as bacteria [e.g., Escherichia species (e.g., E. coli), Bacillus species (e.g., B. subtilis), Salmonella species, or Mycobacterium (preferably non-pathogenic, e.g., M. bovis BCG), yeast (e.g., Saccharomyces cerevisiae, Pichia pastoris), and protozoa]. Alternatively, the transformed cells can be derived from multicellular organisms, i.e., animal cells such as fungal cells, insect cells, algal cells, plant cells, or mammalian cells. For the purpose of cloning and / or optimized expression, it is preferred that the transformed cells can replicate the nucleic acid fragment of the present invention. Cells expressing the nucleic acid fragment can be used for the small-scale or large-scale preparation of the peptide of the present invention.

[0220] When a precursor peptide is produced by a transformed cell, it is not essential but convenient for the expression product to be secreted into the medium.

[0221] Medical condition In a broad embodiment, the present invention provides a compstatin analog of the present invention for use as a medicament or for treatment.

[0222] The compstatin analogs described herein have biological activity of binding to C3 protein and / or inhibiting complement activation. Generally, the compstatin analogs of the present invention can be used in the treatment or prevention of conditions associated with excessive or unwanted activation of the complement system. Complement is activated via three different pathways, namely the classical pathway, the lectin pathway, and the alternative pathway. The major activation event common to all three pathways is the proteolytic cleavage of the central protein of the complement system, C3, into the activation products C3a and C3b by C3 convertase. The generation of these fragments leads to the opsonization of pathogenic cells by C3b and iC3b, a process that renders them susceptible to phagocytosis or clearance and results in the activation of immune cells via interaction with complement receptors (Markiewski & Lambris, 2007, Am. J. Pathol., 171: 715-727). The deposition of C3b on target cells also induces the formation of new convertase complexes, thereby initiating an autoamplification loop. Assemblies of proteins bound to plasma and cell surfaces carefully regulate complement activation to prevent self-attack of host cells by the complement cascade. The 13-amino acid cyclic tridecapeptide used as a reference point for the design of the compstatin analogs of the present invention inhibits complement activation by binding to C3 and / or C3b and prevents the cleavage of native C3 by C3 convertase. Without wishing to be bound by any particular theory, the inventors believe that the compstatin analogs of the present invention also function in this manner and may share one or more biological activities selected from (1) binding to C3 protein, (2) binding to C3b protein, (3) inhibition of the cleavage of native C3 by C3 convertase, and / or (4) inhibition of complement system activation. The biological activity of the compstatin analogs of the present invention can be measured in vitro, for example, using the protocol shown in the following examples, by measuring the inhibitory effect on the classical complement pathway in a hemolysis assay.

[0223] Excessive complement activation or inappropriate regulation can cause many pathological conditions ranging from autoimmune diseases to inflammatory diseases (Holers, 2003, Clin. Immunol., 107: 140-51; Markiewski & Lambris, 2007, supra; Ricklin & Lambris, 2007, Nat. Biotechnol., 25: 1265-75; Sahu et al., 2000, J. Immunol., 165: 2491-9). These conditions include the following: (1) inhibiting complement activation to promote the treatment of diseases or conditions including age-related macular degeneration, Stargardt's disease, periodontitis, diabetic retinopathy, glaucoma, uveitis, rheumatoid arthritis, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, cancer, respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), allergic inflammation, emphysema, bronchitis, bronchiectasis, cystic fibrosis, tuberculosis, pneumonia, respiratory distress syndrome (RDS - neonatal and adult), rhinitis and sinusitis; bacterial infections such as sepsis, ischemia-reperfusion injury in various tissues, myocardial infarction, anaphylaxis, paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, psoriasis, hidradenitis suppurativa, myasthenia gravis, systemic lupus erythematosus, CHAPLE syndrome, C3 glomerulopathy, uremic syndrome, Crohn's disease, ulcerative colitis, antiphospholipid antibody syndrome; or (2) inhibiting complement activation that occurs during cell or solid organ transplantation, or during the use of artificial organs or implants (e.g., by coating cells, organs, artificial organs or implants with the peptides of the present invention or treating them in other ways); or (3) inhibiting complement activation that occurs in extracorporeal shunts of physiological fluids (blood, urine) (e.g., by coating the tubes through which the fluid is shunted with the compstatin analogs of the present invention).

[0224] Pharmaceutical composition and administration In a further embodiment, the present invention relates to a composition comprising a compstatin analog according to the present invention, or a pharmaceutically acceptable salt or solvate thereof, together with a carrier. In one embodiment of the present invention, the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition comprising a compstatin analog according to the present invention, or a salt and / or solvate thereof, together with a carrier, excipient or vehicle. Accordingly, the compstatin analog of the present invention, or a salt or solvate thereof, particularly a pharmaceutically acceptable salt and / or solvate thereof, can be formulated for storage or administration and formulated as a composition or pharmaceutical composition comprising a therapeutically effective amount of the compstatin analog of the present invention, or a salt or solvate thereof.

[0225] Suitable salts formed with bases include metal salts such as alkali metal or alkaline earth metal salts.

[0226] In one embodiment, the pharmaceutical composition of the present invention is one in which the compstatin analog is in the form of a pharmaceutically acceptable acid addition salt.

[0227] As will be apparent to those skilled in the art, the "therapeutically effective amount" of the compstatin analog compound of the present invention or its pharmaceutical composition will vary particularly depending on the age, weight and / or gender of the subject (patient) being treated. Other factors that may be relevant include the physical characteristics of the particular patient under consideration, the patient's diet, the nature of any co-medication, the particular compound used, the particular mode of administration, the desired pharmacological effect, and the particular therapeutic indication. These factors and their relationships in determining this amount are well known in the medical field, so the determination of therapeutically effective dosage levels, the amount necessary to achieve the desired result of treating and / or preventing and / or correcting the malabsorption and / or mild inflammation described herein, and the determination of other medical indications disclosed herein are within the scope of those skilled in the art.

[0228] As used herein, the term "therapeutically effective amount" refers to an amount that reduces a given condition or symptom of a pathology and preferably normalizes the physiological response in an individual having that condition or pathology. Reduction of symptoms or normalization of physiological response can be determined using routine methods in the art and may vary depending on the given condition or pathology. In one embodiment, a therapeutically effective amount of one or more compstatin analogs or a pharmaceutical composition thereof restores a measurable physiological parameter to substantially the same value (preferably within 30%, more preferably within 20%, even more preferably within 10%) of the parameter in an individual without the condition or pathology in question.

[0229] In one embodiment of the invention, administration of the compounds or pharmaceutical compositions of the invention is initiated at a lower dosage level, which is increased until the desired effect of preventing / treating the relevant medical indication is achieved. This will define a therapeutically effective amount. For the compstatin analogs of the invention, alone or as part of a pharmaceutical composition, the human dosage of such active compstatin analogs can be about 0.01 pmol / kg to 500 μmol / kg body weight, about 0.01 pmol / kg to 300 μmol / kg body weight, 0.01 pmol / kg to 100 μmol / kg body weight, 0.1 pmol / kg to 50 μmol / kg body weight, 1 pmol / kg to 10 μmol / kg body weight, 5 pmol / kg to 5 μmol / kg body weight, 10 pmol / kg to 1 μmol / kg body weight, 50 pmol / kg to 0.1 μmol / kg body weight, 100 pmol / kg to 0.01 μmol / kg body weight, 0.001 μmol / kg to 0.5 μmol / kg body weight, 0.05 μmol / kg to 0.1 μmol / kg body weight.

[0230] Of course, the most suitable therapeutic dosage and treatment regimen for a patient will vary depending on the disease or condition being treated, as well as the patient's weight and other parameters. Without wishing to be bound by any particular theory, dosages in the range of mg / kg, and shorter or longer durations or frequencies of treatment, are expected to result in therapeutically useful outcomes such as a statistically significant inhibition of the alternative and classical complement pathways. The dosage and method of administration most suitable for human use are guided by the results obtained according to the present invention and can be confirmed in appropriately designed clinical trials.

[0231] Effective dosages and treatment protocols can be determined by conventional means that start with low dosages in experimental animals and then increase the dosage while monitoring the effects and similarly varying the treatment regimen systematically. Many factors can be considered by the clinician when determining the optimal dosage for a given subject.

[0232] For topical delivery to the eye, the pharmaceutically acceptable composition can be formulated in isotonic pH-adjusted sterile saline or water, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition can be formulated as an ointment such as petrolatum or an eye drop. Methods of topical administration to the eye include, for example, intravitreal injection, transscleral injection, or placement of a scleral patch, selective arterial catheterization, eye drops or eye ointments, transretinal, subconjunctival, intravitreal injection, suprachoroidal injection, subtenon injection, scleral pocket and scleral incision injection, osmotic pumps, and the like. The agent can also be administered, instead, by intravascular administration such as intravenous (IV) or intraarterial. For intravitreal injection and scleral patching, the clinician uses a topical approach to the eye after initiating appropriate anesthesia, including analgesics and cycloplegics. A needle containing the therapeutic compound is directed and inserted aseptically into the target choroid or sclera. When the needle is properly positioned, the compound is injected into either or both the choroid and sclera. When using any of these methods, the clinician can select a sustained-release formulation or a long-acting formulation. Thus, depending on the subject's tolerance and response to treatment, this procedure can be repeated only every few months or years.

[0233] The following examples are provided to explain the present invention in more detail. They are intended to illustrate rather than limit the present invention.

Example

[0234] Example 1: Synthesis of compstatin analog General peptide synthesis

[0235]

Table 1

[0236] Equipment and synthetic strategy The peptide was synthesized batchwise on a peptide synthesizer such as a CEM Liberty peptide synthesizer or a Symphony X synthesizer according to the solid-phase peptide synthesis method using 9-fluorenylmethyloxycarbonyl (Fmoc) as the N-α-amino protecting group and appropriate common protecting groups for side-chain functionality.

[0237] As the polymer support-based resin, for example, TentaGel™ M was used. The synthesizer was charged with the resin swollen in DMF before use.

[0238] Coupling CEM Freedom peptide synthesizer A solution of Fmoc-protected amino acid (4 eq) was added to the resin together with a coupling reagent solution (4 eq) and a base solution (8 eq). The mixture was heated to 70 - 75 °C by a microwave unit and coupled for 5 minutes, or coupled for 60 minutes without heating. During coupling, nitrogen was bubbled through the mixture.

[0239] Symphony X synthesizer The coupling solution was transferred to the reaction vessel in the following order: amino acid (4 eq), HATU (4 eq), and DIPEA (8 eq). The coupling time was 10 minutes at room temperature (RT) unless otherwise specified. The resin was washed with DMF (5 × 0.5 minutes). In the case of repeated coupling, the coupling time was 45 minutes at room temperature in all cases.

[0240] Deprotection CEM Freedom peptide synthesizer The Fmoc group was deprotected using piperidine in DMF or other suitable solvents. The deprotection solution was added to the reaction vessel and the mixture was heated for 30 seconds. The reaction vessel reaching about 40 °C was drained, fresh deprotection solution was added, then heated to 70 - 75 °C for 3 minutes, drained from the reaction vessel, and the resin was washed with DMF or other suitable solvents.

[0241] Symphony X synthesizer Fmoc deprotection was carried out using 40% piperidine in DMF for 2.5 minutes and repeated using the same conditions. The resin was washed with DMF (5 × 0.5 minutes).

[0242] Side chain acylation Fmoc-Lys(Dde)-OH or another amino acid with an orthogonal side-chain protecting group was introduced at the position of acylation (side-chain lipidation). The N-terminus of the linear peptide was protected with Ac or Boc. While the peptide was still attached to the resin, the orthogonal side-chain protecting group was selectively cleaved using freshly prepared hydrazine hydrate (2 - 4%) in NMP for 2 × 15 minutes. Subsequently, the unprotected lysine side-chain was extended using standard coupling conditions and Fmoc-deprotection with the desired building blocks. The lipidated moiety was coupled as the final step.

[0243] Cleavage The dried peptide resin was treated with TFA and appropriate scavengers for about 2 hours. The volume of the filtrate was reduced and the crude peptide was precipitated after the addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried.

[0244] HPLC purification of crude peptide The crude peptide was purified using preparative reverse-phase HPLC with a fraction collector using a conventional HPLC apparatus such as a Gilson GX-281 with a 331 / 332 pump combination for binary gradient application, equipped with a column such as a 5 × 25 cm Gemini NX 5u C18 110A column, and a flow rate of 20 - 40 ml / min using appropriate gradients of buffer A (0.1% aqueous formic acid) or A (0.1% aqueous TFA) and buffer B (0.1% formic acid, 90% MeCN, aqueous solution) or B (0.1% TFA, 90% MeCN, aqueous solution). The fractions were analyzed by analytical HPLC and MS, the selected fractions were pooled and lyophilized. The final product was characterized by HPLC and MS.

[0245] Oxidation After purification and lyophilization of the linear peptide, the peptide was redissolved in 0.1% TFA / water, acetonitrile, and acetic acid to a clear solution. The concentration of the peptide solution was maintained at about 1 - 2 mg / ml depending on the ability to solubilize the peptide. The peptide solution was stirred while a methanol solution of iodine (about 1.5 equivalents) was added dropwise until the peptide solution turned orange. After 10 - 15 minutes, the oxidation was completed and the excess iodine was reduced with an ascorbic acid solution (1 equivalent) in water until a colorless peptide solution was obtained. The peptide solution was diluted with water before preparative HPLC purification.

[0246] Analytical HPLC The final purity was measured by analytical HPLC (Agilent 1100 / 1200 series) equipped with an autosampler, a degasser, a 20 μl flow cell, and Chromeleon software. The HPLC was operated at a flow rate of 1.2 ml / min at 40 °C using an analytical column such as a Kinetex 2.6 μm XB-C18 100A 100×8.6 mm column. The compounds were detected and quantified at 215 nm. Buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution).

[0247] Mass spectrometry The final MS analysis was measured by, for example, conventional mass spectrometry. It was equipped with a Waters Xevo G2 TOF, an electrospray detector with lock mass calibration, and MassLynx software. It was operated in positive mode using direct injection and a cone voltage of 15 V (1TOF), 30 V (2TOF), or 45 V (3TOF) as defined in the chromatogram. The accuracy was 5 ppm and the typical resolution was 15,000 - 20,000.

[0248] Synthesis of Compound No. 24: Ac-IC(1)IWQDWGEHRC(1)TEGE-NH 2 Solid-phase peptide synthesis was performed on a Symphony X Synthesizer using standard Fmoc chemistry. Prior to use, TentaGel S RAM (2.51 g; 0.23 mmol / g) was swollen in DMF (20 ml) and the Fmoc-group was deprotected according to the above procedure.

[0249] Coupling The appropriate protected Fmoc-amino acids according to the sequence were coupled as above using HATU as the coupling reagent. All couplings were carried out at R.T.

[0250] Deprotection Fmoc deprotection was carried out according to the above procedure.

[0251] Cleavage of peptide from solid support The peptide-resin was washed with EtOH (3 × 10 ml) and Et 2 O (3 × 10 ml) and dried at room temperature to a constant weight. The peptide was cleaved from the resin by treatment with TFA / DODT (95 / 5; 60 ml, 2 h; r.t), the volume of the filtrate was reduced, and the crude peptide was precipitated after the addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried at room temperature to a constant weight to obtain 760 mg of a crude peptide product (purity ~30%).

[0252] HPLC purification of crude linear peptide The crude peptide was purified by preparative reverse-phase HPLC using a combination of Gilson GX-281 and 331 / 332 pumps for binary gradient application equipped with a 5×25 cm Gemini NX 5u C18 110A column and a fraction collector, flowing at 35 ml / min with a gradient from 20% B to 45% B in 47 minutes using buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution). The fractions were analyzed by analytical HPLC and MS, the relevant fractions were pooled, and lyophilized to obtain 190 mg with a purity of 190 mg as characterized by HPLC and MS as described above. The calculated monoisotopic MW = 2001.58 and the observed value was 2001.81.

[0253] Oxidation of crude linear peptide 190 mg of the purified linear peptide was dissolved in 220 ml of 0.1% TFA in water (65%) and acetonitrile (35%) until a clear solution was obtained. The peptide solution was stirred during the addition of an iodine methanol solution (2.2 mL, approximately 1.5 equivalents). Iodine was added dropwise until the peptide solution turned orange. Analytical HPLC was performed following the reaction, but oxidation was already complete after 10 - 15 minutes. Excess iodine was reduced using an aqueous solution of ascorbic acid (220 μL, approximately 1 equivalent) until a colorless peptide solution was obtained. The peptide solution was slightly reduced by rotary evaporation before purification by preparative HPLC.

[0254] HPLC purification of oxidized peptide The crude peptide was purified by preparative reverse-phase HPLC using a combination of Gilson GX-281 and 331 / 332 pumps for binary gradient application equipped with a 5×25 cm Gemini NX 5u C18 110A column and a fraction collector, flowing at 35 ml / min with a gradient of 20% B to 45% B in 47 minutes using buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution). The fractions were analyzed by analytical HPLC and MS, the relevant fractions were pooled and lyophilized to obtain 138 mg, which had a purity of 92% and was characterized by HPLC and MS as described above. The calculated monoisotopic MW = 1999.83 and the observed value was 1999.54.

[0255] Synthesis of Compound 119 Ac-SEFC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]G[Peg3][γGlu][Peg3])-NH 2 Solid-phase peptide synthesis was performed on a Symphony X Synthesizer using standard Fmoc chemistry. Before use, TentaGel S RAM (3× ca. 1.3 g; 0.22 mmol / g) was swollen in DMF (3×10 ml) and the Fmoc-group was deprotected according to the above procedure.

[0256] Coupling The appropriate protected Fmoc-amino acids according to the sequence were coupled as described above using HATU as the coupling reagent. All couplings were performed at R.T. The lysine used for the incorporation of the branched part was incorporated as Fmoc-Lys(Dde)-OH for orthogonal coupling.

[0257] Deprotection Fmoc deprotection was carried out according to the above procedure.

[0258] Side chain acylation While the peptide was still attached to the resin, the orthogonal side-chain protecting group (Dde) was selectively cleaved using freshly prepared hydrazine hydrate (2 - 4%) in NMP for 2 x 15 minutes. The unprotected lysine side-chain was double-bonded with Fmoc-Peg3-OH, followed by single couplings with Fmoc-Glu-OtBu, Fmoc-Peg3-OH, Fmoc-Gly-OH, Fmoc-Glu-OtBu, and finally a single coupling with the fatty acid moiety 17-carboxy-heptadecanoic acid monobutyl ester using standard coupling conditions.

[0259] Cleavage of peptide from solid support The peptide-resin was washed with EtOH (3 x 15 ml) and Et 2 O (3 x 150 ml) and dried to a constant weight at room temperature. The peptide was cleaved from the resin by treatment with TFA / DODT (95 / 5; 120 ml, 2 hours; r.t.). The volume of the filtrate was reduced and the crude peptide was precipitated after the addition of diethyl ether. The crude peptide precipitate was washed several times with diethyl ether and finally dried to a constant weight at room temperature to obtain 2.36 g of the crude peptide product (purity ~41 - 48%).

[0260] HPLC purification of crude linear peptide The crude peptide was purified by preparative reverse-phase HPLC using a combination of Gilson GX-281 and 331 / 332 pumps for binary gradient application equipped with a 5 x 25 cm Gemini NX 5u C18 110A column and a fraction collector, flowing at 35 ml / min with a gradient from 30% B to 60% B in 47 minutes using buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution). The fractions were analyzed by analytical HPLC and MS, the relevant fractions were pooled, and lyophilized to obtain 744 mg at a purity of 744 mg as characterized by HPLC and MS as described above. The calculated monoisotopic MW = 3207.47 and the observed value was 3207.32.

[0261] Oxidation of crude linear peptide 744 mg of the purified linear peptide was dissolved in 350 ml of 0.1% TFA in water, 150 ml of acetonitrile and 100 ml of acetic acid to a clear solution (total volume 600 ml). The peptide solution was stirred while adding it dropwise to a methanol solution of iodine (4.7 mL, about 1.5 equivalents). Iodine was added dropwise until the peptide solution turned orange. Analytical HPLC was performed following the reaction, but oxidation was already complete after 10 - 15 minutes. Excess iodine was reduced using an aqueous solution of ascorbic acid (150 μL, about 1 equivalent) until a colorless peptide solution was obtained. Before purification by preparative HPLC, the peptide solution was slightly reduced by rotary evaporation.

[0262] HPLC purification of oxidized peptide The crude peptide was purified by preparative reverse-phase HPLC using a combination of Gilson GX-281 and 331 / 332 pumps for two-component gradient application equipped with a 5×25 cm Gemini NX 5u C18 110A column and a fraction collector, flowing at 35 ml / min with a gradient from 30% B to 60% B in 47 minutes using buffer A (0.1% TFA, aqueous solution) and buffer B (0.1% TFA, 90% MeCN, aqueous solution). The fractions were analyzed by analytical HPLC and MS, the relevant fractions were pooled, and lyophilized to obtain 510 mg with a purity of 91% as characterized by HPLC and MS as described above. The calculated monoisotopic MW = 3205.47 and the observed value was 3205.23.

[0263]

Table 2-1

[0264]

Table 2-2

[0265]

Table 2-3

[0266]

Table 2-4

[0267]

Table 2-5

[0268]

Table 2-6

[0269]

Table 2-7

[0270] Example 2: In vitro hemolysis test Method The in vitro effect of the compound of the present invention was evaluated by measuring the inhibitory effect on the classical complement pathway in a hemolysis assay.

[0271] Briefly, the compound of the present invention and the reference compound were dissolved in DMSO and used as a nine-point serial dilution in a 96-well plate in Tris / Casein assay buffer (10 mM Tris, 145 mM NaCl, 0.5 mM MgCl 2 , 0.15 mM CaCl 2and diluted in 0.1% W / V casein, adjusted to pH 7.4). Sensitized sheep red blood cells (RBC) coated with rabbit anti-sheep red blood cell antiserum (Complement Technology, Inc., TX, USA) were washed with Tris / casein assay buffer. 50 μL was added from each well of the diluted compound to a 96-well plate containing 50 μL of diluted human serum (Complement Technology, Inc., TX, USA) and incubated at room temperature for 15 minutes. The serum dilution factor was optimized for each serum batch to obtain 70 - 90% of maximum hemolysis using the protocol. Next, 50 μL of sensitized sheep red blood cells (107 cells per well) was added to all wells. After incubation for 30 minutes with gentle stirring at 37 °C, the reaction was stopped by adding 50 μL of Tris STOP buffer (10 mM EDTA, 10 mM Tris, 145 mM NaCl adjusted to pH 7.4) per well. The red blood cells were then removed by centrifugation, and the resulting supernatant was measured for hemolysis by absorbance at 405 nm.

[0272] The reaction was normalized against positive and negative controls (solvent), and the IC50 was calculated from the concentration-response curve using a four-parameter logistic (4PL) non-linear model for curve fitting. All values are based on independent determinations with n > 2.

[0273]

Table 3

[0274] Additional compounds were tested as shown below.

[0275]

Table 4-1

[0276]

Table 4-2

[0277]

Table 4-3

[0278]

Table 4-4

[0279]

Table 4-5

[0280] Pairs of the following compounds, each differing only at the 3-position, show that the effect of substituting valine with isoleucine is seen in compounds having various peptide backbone sequences.

[0281]

Table 5

[0282] It was also shown that isoleucine at the 3-position is superior to other residues that are often considered "conservative" substitutions of isoleucine.

[0283]

Table 6

[0284] Due to the high C3 concentration in serum, it would be difficult to use a hemolysis assay to distinguish between compounds having very high affinity for C3.

[0285] In such a situation, as described below, it may be possible to determine a more accurate hierarchy of binding affinities for C3 by SPR measurements using immobilized C3.

[0286] Example 3: Solubility test Materials and methods Solubility of the compound at 10 mg / mL The solubility of the compound was evaluated by measuring light scattering between pH 4 and pH 7.5. The compound was dissolved in a stock solution of 20 mg / mL in H 2 O at pH 2.5 or pH 10. These stock solutions were diluted 1:1 with 200 mM buffer solution to reach a final solution of 10 mg / mL compound in 100 mM buffer. The five conditions examined were (1) acetate pH 4.0, (2) acetate pH 5.0, (3) phosphate pH 6.0, (4) phosphate pH 7 and (5) phosphate pH 7.5.

[0287] These samples were equilibrated for 15 minutes at ambient temperature before evaluating solubility by visual inspection and absorbance measurement in a SpectraMax 190 microplate reader (Molecular Devices).

[0288] Visual inspection Visual inspection included manually checking the 96-well plate for transparent or non-transparent wells. In addition to this, a photograph of the 96-well plate was taken.

[0289] Microplate reader and light scattering Absorbance was measured at four wavelengths of 280 nm, 325 nm, 340 nm and 360 nm in a UV-transparent 96-well microplate in a SpectraMax 190 microplate reader (Molecular Devices). The compound does not absorb at 325 - 360 nm, and thus the signal at these wavelengths is an expression of light scattering reflecting the presence of visible or sub-visible particles detected as an increased signal.

[0290] Light scattering was normalized to the signal from pure buffer (100 mM), and compound solubility was evaluated as good (+) or poor (-). This criterion is a combination of visual inspection and light scattering of less than 0.1 AU, and values less than 0.1 AU are good in visually transparent samples.

[0291] Solubility of Compound 24: Stock solution Compound 24 was carefully weighed and dissolved in pH 2.5 H 2 O-Cl. The stock solution was equilibrated at ambient temperature for 15 minutes, and at this point there were no visible particles. 200 mM buffer stock solutions were prepared for each pH condition.

[0292] Solubility test: Formulations for the solubility test were prepared by gently mixing 50 μL of the compound 24 stock solution and 50 μL of the buffer stock solution by pipetting twice. This was done for each buffer / pH condition in a UV-transparent 96-well microplate (Corning 96-well REF 3635). For pH 2.5 H 2 O-Cl, a reference sample without compound 24 was prepared by mixing 50 μL with 50 μL of the buffer stock solution. Before evaluating solubility, the plate was covered with a lid and left at ambient temperature for 15 minutes.

[0293] Measurement of solubility: Solubility was evaluated by visual inspection of each formulation and photographs taken in a photo box. Light scattering was measured at 280 nm, 325 nm, 340 nm, and 360 nm using a SpectraMax 190 microplate reader (Molecular Devices).

[0294] As a result of visual inspection, states 1, 2, and 3 were cloudy, and state 2 further contained visible precipitates. By absorbance measurement, it was visually confirmed that all of conditions 1, 2, and 3 exceeded the 0.1 AU threshold. Thus, conditions 4 and 5 were considered to be good conditions for the solubility of 10 mg / mL of compound 24.

[0295] Similarly, the solubility of other compounds was also tested (Table 6).

[0296]

Table 7-1

[0297]

Table 7-2

[0298]

Table 7-3

[0299] Example 4: Affinity Measurement by Surface Plasmon Resonance (SPR) Method The peptides were characterized for their binding affinity (Kd) to C3 using surface plasmon resonance (SPR). Human C3 (Complement tech #A113c) was immobilized onto individual flow cells of a CM5 sensor chip (GE Healthcare) using standard amine coupling to a density of approximately 3000 resonance units (RU) in a buffer consisting of 10 mM phosphate pH 7.4, 150 mM NaCl, and 0.05% Tween20.

[0300] Interaction experiments were performed using a Biacore T200™ instrument (GE Healthcare) at 25 °C using a multi-cycle experiment approach. Peptides were injected in increasing concentration series (6 - 8 different concentrations) at a flow rate of 30 μL / min for 60 - 120 s in a buffer consisting of 10 mM Tris buffer pH 7.4, 150 mM NaCl, and 0.05% Tween20. This was followed by a dissociation period of up to 10 min. The C3 surface was regenerated between runs by injection of 3M MgCl 2 for 45 s.

[0301] Sensorgrams were double referenced (reference surface, blank) prior to analyzing the kinetic profiles by globally fitting the data to a 1:1 Langmuir binding model to obtain the association and dissociation rates for calculation of the equilibrium dissociation constant Kd. Each peptide was tested in at least 3 independent experiments.

[0302]

Table 8-1

[0303]

Table 8-2

[0304] Pairs of the following compounds differ only at the 3-position and show the effect of substituting valine with isoleucine with different peptide backbones.

[0305]

Table 9

[0306] Example 5: Profiling of Test Compounds in Non-Human Primates (NHPs) Each test substance was administered as a single subcutaneous injection to healthy male cynomolgus monkeys (Macaca fascicularis). The compounds were formulated in 20 mM phosphate and mannitol adjusted to pH 7.5 with NaOH for isotonicity and administered at 1840 nmol / kg. Blood was collected from each animal from the femoral vein at pre-dose, 1, 2, 4, 8, 24, 48, 72, 96, and 120 hours (10 samplings). Blood was collected into serum separation tubes and allowed to clot at room temperature. The tubes were centrifuged, and the resulting serum was aliquoted, snap frozen on dry ice, and stored nominally at -80°C until analysis. All NHP tests were conducted in accordance with laws and regulations regarding animal welfare, including approval of the tests by the local ethics review process.

[0307] At specific time points after administration, sera isolated from non-human primates were analyzed for alternative pathway complement activity using the Svar Life Science (formerly Euro Diagnostica AB, Sweden) Complement Alternative Pathway WIESLAB® kit according to the manufacturer's protocol. Briefly, serum samples or controls were diluted in buffer and incubated in microtiter strips coated with a specific activator of the alternative pathway. The wells were washed and C5b-9 was formed using the included colorimetric reagent. Absorbance was measured at 405 nm. The percentage of activity of the alternative complement pathway was calculated for each animal and for each time point relative to the pre-administration activity (0 hours) of each animal, subtracting the negative control. This reflects the pharmacological activity of the compound.

[0308] The results of the alternative pathway WIESLAB® kit are shown in FIGS. 1a-f. In FIG. 1a, non-acylated compound 61 had a relatively short duration of action despite its high affinity for C3. The same was true for non-acylated compound Cp40 (FIG. 1b) and compound 54 (FIG. 1e). In contrast, the acylated compounds in FIGS. 1b, 1c, 1d, 1e, and 1f generally had a longer-lasting pharmacological activity in vivo despite their lower affinity compared to the non-acylated compounds. Acylation of peptides is generally known to increase the in vivo half-life, but surprisingly, it was found that the in vivo duration of pharmacological efficacy was extended to this extent.

[0309] To evaluate the pharmacokinetic half-life (t1 / 2), serum samples isolated from non-human primates at specific time points after administration were analyzed for all drug compounds after sample preparation by solid-phase extraction (SPE) and liquid chromatography mass spectrometry (LC-MS / MS) using an analog internal standard. A single measurement of the concentration in serum was used for the calculation of pharmacokinetic parameters using the non-compartmental approach of Phoenix WinNonlin 6.3. The plasma terminal elimination half-life (t1 / 2) was determined as ln(2) / λz, where λz is the magnitude of the slope of the logarithmic linear regression of the log concentration vs. time profile at the terminal phase.

[0310] The pharmacokinetic (PK) data are shown in Table 9.

[0311] [Table 10]

Claims

1. Ac-IC(1) IWQDWGEHRC(1) T-NH ２ (Compound 2) Ac-ESS AIC(1) IWQDWGEHRC(1) T-NH ２ (Compound 3) Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)T-NH ２ (Compound 4) Ac-IC(1)IWQKWGEHRC(1)T-NH ２ (Compound 7) Ac-YC(1)IWQDWEHRC(1)T-NH ２ (Compound 9) Ac - ESSAYC(1) IWQDWGEHRC(1) T - NH ２ (Compound 10) Ac-[Sar]C(1)IWQDWEHRC(1)T-NH ２ (Compound 11) Ac-IC(1) IWQDWGEHRC(1) [Sar]-NH ２ (Compound 13) Ac-ESSAC(1) IWQDWGEHRC(1) TGAS-NH ２ (Compound 14) Ac-IC(1) IWQDWGEHRC(1) TGAES-NH ２ (Compound 15) Ac-IC(1) IWQEWGEHRC(1) T-NH ２ (Compound 16) Ac-IC(1) IWQDWGEHSC(1) T-NH ２ (Compound 20) Ac-IC(1) IWQDWGEHRC(1) S-NH ２ (Compound 21) Ac-IC(1) IWQDWGEHRC(1) E-NH ２ (Compound 22) Ac-FC(1) IWQDWGEHRC(1) T-NH ２ (Compound 23) Ac-IC(1) IWQDWGEHRC(1) TEGENH ２ (Compound 24) Ac-IC(1) IWQDWGEHRC(1) TEA-NH ２ (Compound 25) Ac-IC(1) IWQDWGEHRC(1) TE-NH ２ (Compound 26) Ac-IC(1) IWQDWGEHRC(1) EGE-NH ２ (Compound 27) Ac-EGSAIC(1)IWQDWEHRC(1)[Sar]E-NH ２ (Compound 28) Ac-EGSAIC(1)IWQDWEHRTC(1)T-NH ２ (Compound 29) Ac-EGEIC(1)IWQDWEHRC(1)T-NH ２ (Compound 30) Ac-ESEIC(1)IWQDWGHRc(1)T-NH ２ (Compound 31) Ac-SEIC(1) IWQDWGEHRC(1) TEA-NH ２ (Compound 32) Ac-EIC(1)IWQDWGHR C(1)TE-NH ２ (Compound 33) Ac-EIC(1)IWQDWEHRC(1)TEGE-NH ２ (Compound 34) Ac-EGEIC(1)IWQDWEHRC(1)EGE-NH ２ (Compound 35) Ac-ESEIC(1)IWQDWGHR C(1)EGE-NH ２ (Compound 36) Ac-KEKIC(1)IWQDWEHRC(1)TEKE-NH ２ (Compound 37) Ac-EKGIC(1)IWQDWEHRC(1)TEKP-NH ２ (Compound 38) Ac-IC(1) IWQDWGEHRC(1) TEGK-NH ２ (Compound 39) Ac-GS[Aic(1)]IWQDWEHRC(1)[Sar]E-NH ２ (Compound 40) Ac-SAIC(1)IWQDWEHRC(1)[Sar]E-NH ２ (Compound 41) Ac-SAIC(1)IWQDWEHRC(1)TEG-NH ２ (Compound 42) Ac-FC(1)IWQDWEHRC(1)TGAE-NH ２ (Compound 43) Ac-EGSAIC(1)IWQDWEHRC(1)[Sar]EGE-NH ２ (Compound 44) Ac-EGSAFC(1)IWQDWGHR C(1)[Sar]E-NH ２ (Compound 45) Ac-EGSAIC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]E-NH ２ (Compound 49) Ac-EGS AIC(1)I[2-Nal]QDWEHRC(1)[Sar]E-NH ２ (Compound 50) Ac-IC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH ２ (Compound 51) Ac-IC(1)I[2-Nal]QDWGEHRC(1)TGAES-NH ２ (Compound 52) Ac-EGSAFC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]E-NH ２ (Compound 53) Ac-EGSAYC(1)I[1-Me-Trp]QDWGHR C(1)[Sar]E-NH ２ (Compound 54) Ac-EGSAIC(1)IWQDWEHRC(1)TE-NH ２ (Compound 55) Ac-EGSAFC(1)I[1-Nal]QDWEHRC(1)TE-NH ２ (Compound 56) Ac-EGSAFC(1)I[1-Me-Trp]QDWEHRC(1)TE-NH ２ (Compound 57) Ac-EGSAFC(1)I[1-Me-Trp]QDWEHRC(1)EGE-NH ２ (Compound 58) Ac-EGSAYC(1)I[1-Me-Trp]QDWGHR C(1)TE-NH ２ (Compound 59) Ac-EGSAFC(1)I[2-Nal]QDWEHRC(1)TE-NH ２ (Compound 60) Ac-FC(1)I[1-Me-Trp]QDWEHRC(1)TGAES-NH ２ (Compound 61) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-NH ２ (Compound 62) Ac-Fc(1)I[1-Nal]QDWGEHRC(1)TGAES-NH ２ (Compound 63) Ac-Fc(1)I[2-Nal]QDWGEHRc(1)TGAES-NH ２ (Compound 64) Ac-YC(1)I[2-Nal]QDWEHRC(1)TGAES-NH ２ (Compound 65) Ac-YC(1)IWQDWEHRC(1)TGAES-NH ２ (Compound 66) Ac - SEFC(1)I[1 - Me - Trp]QDWEHRC(1)TGAES - NH ２ (Compound 67) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TEAGS-NH ２ (Compound 68) Ac-YC(1)I[1-Me-Trp]QDWGEHRC(1)TESGA-NH ２ (Compound 69) Ac-EGSAYC(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]E-NH ２ (Compound 70) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA-NH ２ (Compound 71) Ac-FC(1)I[1-Me-Trp]QDW[Sar]EHRC(1)TGAES-NH ２ (Compound 72) H-{d}YFC(1)I[1-Me-Trp]QD W[Sar]EHRC(1)TGAES-NH ２ (Compound 73) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]GAES-NH ２ (Compound 74) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA-NH ２ (Compound 75) Ac-Sefc(1)I[1-Me-Trp]QDW[Sar]Ehrc(1)[Sar]EA-NH ２ (Compound 76) Ac-Sefc(1)I[1-Me-Trp]QDW[Sar]Ehrc(1)TEA-NH ２ (Compound 77) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRc(1)[Sar]E-NH ２ (Compound 78) Ac-Sefc(1)I[1-Me-Trp]Qdw[Sar]Ehrc(1)[Sar]E-NH ２ (Compound 79) Ac-EFC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA-NH ２ (Compound 80) Ac-Ser[Sar]C(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA-NH ２ (Compound 81) Ac-Ser[Sar]C(1)I[1-Me-Trp]QDWGEHR C(1)TEA-NH ２ (Compound 82) Ac-Sefc(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH ２ (Compound 83) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)SEA-NH ２ (Compound 84) Ac-EFC(1)I[1-Me-Trp]QDWEHRC(1)ES-NH ２ (Compound 85) Ac-Sefc(1)I[1-Me-Trp]QDWEHKC(1)[Sar]EA-NH ２ (Compound 86) Ac-GEFC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA-NH ２ (Compound 87) Ac-GE[Sar]C(1)I[1-Me-Trp]QDWEHRC(1)TEA-NH ２ (Compound 88) Ac-Ser[Sar]C(1)I[1-Me-Trp]QEW[Sar]EHR C(1)TEA-NH ２ (Compound 89) Ac-Ser[Sar]C(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EA-NH ２ (Compound 90) H-{d}Y[Sar]C(1)I[1-Me-Trp]QDWGEHRC(1)TEA-NH ２ (Compound 91) A compstatin analog as defined in

1. , wherein the side chain of the residue represented by C(1) is involved in a disulfide bond, or a pharmaceutically acceptable salt and / or solvate thereof.

2. Ac-IC(1) IWQDWGEHRC(1) TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH ２ (Compound 92) Ac-IC(1)IWQDWEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 93) Ac-IC(1) IWQDWGEHRC(1) TEG-E-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 94) Ac-IC(1) IWQDWGEHRC(1) TEG-K((15-carboxy-pentadecanoyl)-[(Piperazine-1-yl)-acetyl][Peg3][Peg3])-NH ２ (Compound 95) Ac-IC(1)IWQDWDGEHR C(1)TEG-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 96) Ac-IC(1) IWQDWGEHRC(1) TEG-E-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 97) Ac-IC(1) IWQDWGEHRC(1) TEG-K([19-carboxy-nonadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 98) [[15 - Carboxy - pentadecanoyl]] - ESSAIC(1)IWQDWEHR C(1)TEGE - NH ２ (Compound 99) Ac-[K([15-carboxy-pentadecanoyl]-[γGlu][Peg3][Peg3])]GSAC(1)IWQDWEHRC(1)TEGE-NH ２ (Compound 100) Ac-EGSAIC(1)IWQDWEHRC(1)TEG-K([15-carboxy-pentadecanoyl][γGlu])-NH ２ (Compound 101) Ac-Fc(1)I[1-Me-Trp]QDWGEHRC(1)TGAES-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 102) Ac-EGSAYC(1)I[1-Me-Trp]QDWEH-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-C(1)[Sar]E-NH ２ (Compound 103) Ac-EGSAYC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EG-K([15-carboxy-pentadecanoyl][γGlu][Peg3][Peg3])-NH ２ (Compound 104) Ac-SAYC(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]E-K([17-carboxy-heptadecanoyl][γGlu]KG[γGlu])-NH ２ (Compound 105) Ac-SAYC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]E-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 106) [[15 - Carboxy - pentadecanoyl]] - EGS EYC(1)I[1 - Me - Trp]QD WGEHRC(1)[Sar]E - NH ２ (Compound 107) [[17-Carboxy-heptadecanoyl]]-EGSEYC(1)I[1-Me-Trp]QDWG EHRC(1)[Sar]E-NH ２ (Compound 108) Ac-EGSAYC(1)I[1-Me-Trp]QDWGHR C(1)[Sar]EGE-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 109) Ac-EGSAYC(1)I[1-Me-Trp]QDWGHR C(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 110) Ac-EGSAYC(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EK[γGlu]-K([17-carboxy-heptadecanoyl][γGlu][Peg3][Peg3])]-NH ２ (Compound 111) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])]-NH ２ (Compound 112) Ac-ASGEYC(1)I[1-Me-Trp]QDWGERC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu)-G[γGlu])-NH ２ (Compound 113) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH ２ (Compound 114) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGK-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH ２ (Compound 115) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGE-K([17-carboxy-heptadecanoyl][γGlu]-K[γGlu])-NH ２ (Compound 116) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 117) Ac-Seyc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[Peg3][γGlu][Peg3])-NH ２ (Compound 118) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G[Peg3][γGlu][Peg3])-NH ２ (Compound 119) Ac - SEFC(1)I[1 - Me - Trp]QEWGEHRC(1)[Sar]EGA - K([17 - carboxy - heptadecanoyl][γGlu] - G[Peg3][γGlu][Peg3]) - NH ２ (Compound 120) Ac-Seyc(1)I[1-Me-Trp]QEW[Sar]Ehrc(1)[Sar]EK[γGlu]A-K([[17-carboxy-heptadecanoyl]][γGlu]G[Peg3][γGlu]-[Peg3])-NH ２ (Compound 121) Ac-Seyc(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGA-K([17-carboxy-heptadecanoyl][γGlu]-G-[Peg3][γGlu][Peg3])-NH ２ (Compound 122) Ac - SEFC(1)I[1 - Me - Trp]QDWEHRC(1)[Sar]EGE[Peg3][Peg3] - K([17 - carboxy - heptadecanoyl][γGlu]G[γGlu]) - NH ２ (Compound 123) Ac-Sefc(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 124) Ac-Seyc(1)I[1-Me-Trp]QEWGEHRC(1)[Sar]EGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 125) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 126) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3][Peg3]-[K[(15-carboxy-pentadecanoyl)[γGlu]G[γGlu]])-NH ２ (Compound 127) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGE[Peg3][Peg3]-[K[(19-carboxy-nonadecanoyl)[γGlu]G[γGlu])-NH ２ (Compound 128) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 129) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)TEGEGGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 130) Ac-SEFC(1)I[1-Me-Trp]QDWEHRC(1)TEGEGGG-K([15-carboxy-pentadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 131) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EK[γGlu]GGG-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 132) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)TEK[γGlu]GGG-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 133) Ac-EFC(1)I[1-Me-Trp]QDWEHRC(1)EGE-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 134) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)TGAES-K([15-carboxy-hexadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 135) Ac - SEFC(1)I[1 - Me - Trp]QDWEHRC(1)TEGE[8 - aminooctanoyl] - K([17 - carboxy - heptadecanoyl][γGlu]G[γGlu]) - NH ２ (Compound 136) Ac - SEFC(1)I[1 - Me - Trp]QDWEHRC(1)TEGE[8 - aminooctanoyl]E - K([17 - carboxy - heptadecanoyl][γGlu]G[γGlu]) - NH ２ (Compound 137) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGE[Peg3]-K([17-carboxy-heptadecanoyl][γGlu]-G[γGlu])-NH ２ (Compound 138) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)[Sar]EGEESES-K([17-carboxy-heptadecanoyl]-[γGlu]G[γGlu])-NH ２ (Compound 139) Ac-Sefc(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 140) Ac - SEFC(1)I[1 - Me - Trp]QDWEHRC(1)[Sar]EGESES - K([17 - carboxy - heptadecanoyl][γGlu]) - NH ２ (Compound 141) Ac-Sefc(1)I[1-Me-Trp]QDWGEHRC(1)TEGE[Peg3]ES-K([17-carboxy-heptadecanoyl][γGlu])-NH ２ (Compound 142) Ac-Sefc(1)I[1-Me-Trp]QDWGEHR[C(1)[Sar]EGE[Peg3][Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 143) Ac-Sefc(1)I[1-Me-Trp]Qdw[Sar]Ehrc(1)[Sar]E[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 144) Ac-EF[C(1)I[1-Me-Trp]QDWEHRC(1)[Sar]EA[Peg3][Peg3]-K([17-carboxy-heptadecanoyl][γGlu]G[γGlu])-NH ２ (Compound 145) A compstatin analog as defined in

2. , wherein the side chain of the residue represented by C(1) is involved in a disulfide bond, or a pharmaceutically acceptable salt and / or solvate thereof.

3. A composition comprising the compstatin analog according to Claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, mixed with a carrier.

4. The composition according to Claim 3, wherein the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising the compstatin analog according to Claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, mixed with a pharmaceutically acceptable carrier, excipient or vehicle.

6. A pharmaceutical composition for inhibiting complement activation, comprising the compstatin analog according to Claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

7. The pharmaceutical composition according to Claim 6, wherein inhibiting complement activation comprises one or more biological activities selected from (1) binding to C3 protein, (2) binding to C3b protein, and / or (3) inhibiting cleavage of native C3 by C3 convertase.

8. A pharmaceutical composition for preventing or treating age-related macular degeneration, Stargardt's disease, periodontitis, diabetic retinopathy, glaucoma, uveitis, rheumatoid arthritis, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, cancer, respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), allergic inflammation, emphysema, bronchitis, bronchiectasis, cystic fibrosis, tuberculosis, pneumonia, respiratory distress syndrome (RDS - neonatal and adult), rhinitis and sinusitis; bacterial infections such as sepsis, ischemia-reperfusion injury in various tissues, myocardial infarction, anaphylaxis, paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, psoriasis, hidradenitis suppurativa, myasthenia gravis, systemic lupus erythematosus, CHAPLE syndrome, C3 glomerulopathy, uremic syndrome, Crohn's disease, ulcerative colitis or antiphospholipid antibody syndrome, which comprises a compstatin analog as claimed in claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

9. A pharmaceutical composition for inhibiting complement activation occurring during cell or organ transplantation, which comprises a compstatin analog as claimed in claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

10. A pharmaceutical composition for use in an ex vivo method for inhibiting complement activation in an extracorporeal shunt of a physiological fluid, which comprises a compstatin analog as claimed in claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof.

11. Use of a compstatin analog as claimed in claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for inhibiting complement activation.

12. Use of a compstatin analog according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating age-related macular degeneration, Stargardt's disease, periodontitis, diabetic retinopathy, glaucoma, uveitis, rheumatoid arthritis, spinal cord injury, stroke, multiple sclerosis, Parkinson's disease, Alzheimer's disease, cancer, respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), allergic inflammation, emphysema, bronchitis, bronchiectasis, cystic fibrosis, tuberculosis, pneumonia, respiratory distress syndrome (RDS - neonatal and adult), rhinitis and sinusitis; bacterial infections such as sepsis, ischemia-reperfusion injury in various tissues, myocardial infarction, anaphylaxis, paroxysmal nocturnal hemoglobinuria, autoimmune hemolytic anemia, psoriasis, hidradenitis suppurativa, myasthenia gravis, systemic lupus erythematosus, CHAPLE syndrome, C3 glomerulopathy, uremic syndrome, Crohn's disease, ulcerative colitis or antiphospholipid antibody syndrome.

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